Involvement of oxysterols in age-related diseases and ageing processes.

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ARR 537 1–15

Ageing Research Reviews xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr

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Involvement of oxysterols in age-related diseases and ageing processes

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Amira Zarrouk a,b,c,d , Anne Vejux a , John Mackrill d , Yvonne O’Callaghan b , Mohamed Hammami c , Nora O’Brien b , Gérard Lizard a,∗ a

Team ‘Biochemistry of Peroxisome, Inflammation and Lipid Metabolism’, EA 7270, University of Bourgogne, INSERM, Dijon, France School of Food and Nutritional Sciences, University College Cork, Cork, Ireland c University of Monastir, Faculty of Medicine, LR12ES05, Lab-NAFS ‘Nutrition—Functional Food & Vascular Health’, Monastir, Tunisia d Department of Physiology, University College Cork, BioSciences Institute, College Road, Cork, Ireland b

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Article history: Received 17 June 2014 Received in revised form 23 September 2014 Accepted 30 September 2014 Available online xxx

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Keywords: Oxysterols Ageing Age-related diseases

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Contents

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Ageing is accompanied by increasing vulnerability to major pathologies (atherosclerosis, Alzheimer’s disease, age-related macular degeneration, cataract, and osteoporosis) which can have similar underlying pathoetiologies. All of these diseases involve oxidative stress, inflammation and/or cell death processes, which are triggered by cholesterol oxide derivatives, also named oxysterols. These oxidized lipids result either from spontaneous and/or enzymatic oxidation of cholesterol on the steroid nucleus or on the side chain. The ability of oxysterols to induce severe dysfunctions in organelles (especially mitochondria) plays key roles in RedOx homeostasis, inflammatory status, lipid metabolism, and in the control of cell death induction, which may at least in part contribute to explain the potential participation of these molecules in ageing processes and in age related diseases. As no efficient treatments are currently available for most of these diseases, which are predicted to become more prevalentdue to the increasing life expectancy and average age, a better knowledge of the biological activities of the different oxysterols is of interest, and constitutes an important step toward identification of pharmacological targets for the development of new therapeutic strategies. © 2014 Published by Elsevier B.V.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxysterols: Origins and structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxysterol-associated aged related diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Age-related macular degeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7. Age related cancers: Colonic and prostatic cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of oxysterols on the ageing process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author. Tel.: +33 380 39 62 56; fax: +33 380 39 62 50. E-mail address: [email protected] (G. Lizard). http://dx.doi.org/10.1016/j.arr.2014.09.006 1568-1637/© 2014 Published by Elsevier B.V.

Please cite this article in press as: Zarrouk, A., et al., Involvement of oxysterols in age-related diseases and ageing processes. Ageing Res. Rev. (2014), http://dx.doi.org/10.1016/j.arr.2014.09.006

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1. Introduction Ageing is considered as an ineluctable biological process, and the lengthening of life expectancy is mainly due to better hygiene, and to major medical progress. This is in agreement with evolutionary theory which considers ageing as the result from a decline in the force of natural selection. Today, in humans, ageing can be considered as a multifactorial process which will depend on genetic and epigenetic factors. Ageing will be influenced by the environmental conditions and the way of life. From a biological point of view, ageing can be commonly defined as the accumulation of diverse deleterious changes occurring in cells and tissues with advancing age that are responsible for the increased risk of disease and death (Harman, 2003). Currently, the major theories of ageing (free radical, immunologic, inflammation, and mitochondrial theories) cannot be considered as mutually exclusive but rather as complementary, and they can provide useful and important insights for the understanding of physiological changes occurring with ageing (Tosato et al., 2007). Due to the increasing life expectancy and average age, it is important to determine the common denominators between the major theories of ageing in order to prevent age related diseases. Ageing in good health is a new challenge with important economic impacts which lead to the concept of silver economy. It is therefore important to identify molecules, and families of molecules, which could play important roles in different aspects of ageing processes and in the development of age related diseases. Among potentially deleterious compounds within the body, some cholesterol oxide derivatives (also named oxysterols) formed endogeneously or present in various foodstuffs have been shown

to play important roles in the metabolism, RedOx equilibrium and inflammatory status of certain cells, especially vascular cells and nervous cells, which are strongly affected by ageing process, and are associated with major age related diseases such as cardiovascular diseases and dementia (Lordan et al., 2009; Vejux and Lizard, 2009; Leoni and Caccia, 2011; Poli et al., 2013). Based on experimental data obtained on cell cultures, animal models, and in humans, there are now several lines of evidence that the function of some major organs (brain, eyes, heart and vessels, colon, pancreas, bones, prostate) can be adversely affected by oxysterols, and that these molecules can contribute to the development of age related diseases (Schroepfer, 2000). Indeed, from a physiological point of view, as hypercholesterolemia frequently increases with age, whereas the oxidative defenses and the hepatic metabolism contributing to reducing the circulating level of oxysterols decrease, it is tempting to speculate that some oxysterols could play critical roles in ageing and in the pathophysiology of several age related diseases such as atherosclerosis, type 2 diabetes mellitus, Alzheimer’s disease (including vascular dementia), age-related macular degeneration and cataract, osteoporosis, and certain forms of cancers (colon carcinoma and prostate cancer) (Fig. 1). 2. Oxysterols: Origins and structures Oxysterols are 27-carbon-atom cholesterol oxidation products. They can be produced endogenously by autoxidation and/or by enzymatic reactions that can modify the sterol nucleus or the isooctyl tail (Otaegui-Arrazola et al., 2010; Iuliano, 2011) (Fig. 2). They also can be provided by food (Otaegui-Arrazola et al., 2010).

Fig. 1. Oxysterols in various age-related diseases. Based on in vitro studies, animal studies and clinical investigations there are several arguments supporting the critical role of various oxysterols in the pathophysiology of age-related diseases such as atherosclerosis, diabetes (especially type 2 diabetes mellitus), vascular dementia, Alzheimer’s disease, age-related macular degeneration and cataract, osteoporosis, and certain forms of cancer (colon carcinoma and prostate cancer).


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Fig. 2. Non enzymatic and enzymatic cholesterol oxidation products. Oxysterols can vary in the type (hydroperoxy, hydroxy, keto, epoxy), number and position of the oxygenated functions introduced and in the nature of their stereochemistry. Examples of derivatives with the A and B rings and the iso-octyl side-chain oxidized are illustrated (http://lipidlibrary.aocs.org/Lipids/chol der/index.htm). Among the oxysterols presented, 7␤-hydroxycholesterol, 7-ketocholesterol, and cholesterol-5␣,6␣-epoxide are major oxysterols resulting from cholesterol autoxidation (non enzymatic oxidation of cholesterol) (Vejux et al., 2011). The other oxysterols, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, and 4␤-hydroxycholesterol result from enzymatic oxidation of cholesterol via the enzymes cholesterol 24-hydroxylase (CYP46A1), cholesterol 25-hydroxylase (Ch25h), cholesterol 27-hydroxylase (CYP27A1), and cholesterol 4␤-hydroxylase (CYP3A4), respectively. Among these enzymes, 25-hydroxylase is not a CYP450 enzyme (Diczfalusy, 2013).

While the nonenzymatic pathways form mainly B-ring oxysterols, the enzymatic pathways can form both B-ring and side-chain hydroxylated oxysterols depending on the enzyme and the tissue. 100 By the nonenzymatic pathways, several oxysterols can be gener101 ated within tissues by oxidative reactions involving different chem102 ical and/or physical agents: reactive oxygen species (ROS), ozone, 103 ultra violet light, metal ions, ferritin and/or other iron-carrying 104 proteins (Iuliano, 2011). These autoxidation processes generate 105 7␣- or 7␤-hydroperoxide, 7␣-hydroxycholesterol (7␣OHC) or 7␤106 hydroxycholesterol (7␤OHC), and 7-ketocholesterol (7KC), 5␣, 6␣107 or 5␤,6␤-epoxycholesterol, as well as cholesterol 3␤,5␣,6␤-triol 108 or cholesterol 3␤, 5␣,6␣-triol depending on pH conditions (Vejux 109 et al., 2011). 7␣OHC and 7␤OHC can arise from the decompo110 sition of 7␣- and 7␤-hydroperoxycholesterol produced by free 111 Q2 radical oxidation of cholesterol (Smith, 1987). Moreover, under cer112 tain chemical conditions in the presence of copper ions, 7␣OHC 113 can be dehydrated and converted in 7KC (Schenck et al., 1957). 114 The interconversion between 7KC and 7␤OHC, initially reported 115 in rat liver (Björkhem et al., 1968), has also been shown to occur 116 in vivo in healthy humans (Larsson et al., 2007). This intercon117 version could be realized by the enzyme 11beta-hydroxysteroid 118 dehydrogenase type 1 (11beta-HSD1) (Odermatt and Klusonova, 119 2014). Indeed; 11beta-HSD1, when transiently expressed in human 120 embryonic kidney 293 cells, revealed the stereo-specific intercon121 version of 7KC to 7␤OHC by rat and human 11beta-HSD1, whereas 122 the hamster enzyme interconverts 7KC to both 7␤OHC and 7␣OHC 123 (Schweizer et al., 2004). 124 By the enzymatic pathways, oxysterols can be generated by a 125 wide number of CYP450 enzymes (Russell, 2000), and some of them 126 are tissue specific. Thus, CYP46A1 (or 24S-hydroxylase) leading to 127 the formation of 24S-hydroxycholesterol (24S-OHC) has been iden128 tified in the brain (Björkhem et al., 1998) and retina (Bretillon et al., 129 98 99

2007). CYP7A1 which catalyzes the formation of 7␣OHC is present in the liver, and involved in bile acid synthesis (Monte et al., 2009). At the opposite extreme, some other CYP450 enzymes are widely expressed. Thus, CYP27A1 (or 27-hydroxylase), which catalyzes the addition of a hydroxyl group on cholesterol to produce 27hydroxycholesterol (27-OHC), is found in most tissues (Pikuleva, 2006). Cholesterol 25-hydroxylase, leading to the formation of 25hydroxycholesterol (25-OHC), is a non-heme iron protein enzyme, also present in many tissues (Lund et al., 1998). Furthermore, oxysterols can be metabolized to bile acids. So, 27-OHC and 25-OHC, are both hydroxylated by oxysterol 7␣hydroxylase (CYP7B1) which is abundant in the liver, and the resulting 7␣-hydroxylated forms are ultimately metabolized to bile acids (Russell, 2000). The oxysterols can be also metabo- Q3 lized to steroid hormones, or other sterols through pathways that may differ according to the type of cell and the mode of experimentation (Schroepfer, 2000). Thus, aminoalkyl oxysterols, such as dendrogenin A, have been described (Khalifa et al., 2014). They are enzymatic compounds resulting from the conjugation of 5␣,6␣-epoxycholesterol and histamine (De Medina et al., 2013). In addition to the classical cholesterol biosynthetic pathway, there exists an alternate bifurcation from squalene oxide. The cyclization of squalene dioxide leads to a series of new oxysterols (Luu, 1995). Therefore, there are several types of structurally different oxysterols. Their characterization as well as their quantification are often difficult, and require painstaking experimentation. Indeed, reliable measurements of oxysterol levels are hampered by low physiological concentrations (approximately 0.01–0.1 ␮M plasma) relative to cholesterol (approximately 5000 ␮M), and by the susceptibility of cholesterol to autoxidation, which can produce artifactual oxysterols (Schroepfer, 2000). So, as oxysterols are challenging molecules to analyze in biological media on account of their


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low abundance against a high background of cholesterol, gas chromatography coupled with mass spectrometry (GC–MS) or liquid chromatography tandem mass spectrometry (LC–MS/MS) are the most reliable methods. Indeed, these techniques give information about the structure of an analyte, and are fairly sensitive, whereas gas chromatography with flame ionization detector (GC-FID) does not give any structural information and is not sensitive enough to quantitate physiologically relevant levels of oxysterols.

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3.1. Atherosclerosis

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Atherosclerosis is an important age related pathology, which can affect the arterial wall of various arteries, and contribute to some serious diseases, especially heart diseases (infarctus), and stroke affecting numerous people. In these severe pathologies, several experimental studies have consistently shown that oxysterols are major compounds capable of favoring the development of atherosclerosis, and that these molecules are able to act at various stages of the atherosclerotic process (Vejux and Lizard, 2009; Shibata and Glass, 2010). 27-OHC is the major oxysterol found in advanced atherosclerotic lesions; its level is approximately proportional to cholesterol levels and increases with increasing severity of atherosclerosis; 7KC is the next most abundant oxysterol, followed by 7␤OHC and 7␣OHC; together, these oxysterols comprise 75–85% of all oxysterols detected in plaques from different sites (Khatib and Vaya, 2014). Before the initiation of the development of atherosclerotic plaque, oxysterols can contribute to the inhibition of vascular relaxation, leading to increased blood pressure. Indeed, some oxysterols such as 7KC present at increased level in oxidized LDL (oxLDL), have been shown to contribute to the endothelial cell dysfunctions that characterize the onset of the atherosclerotic plaque (Deckert et al., 1997, 2002). In addition, as 7KC induces an overproduction of superoxide anion (O2 •− ) in vascular smooth muscle cells (Pedruzzi et al., 2004), this event could also participate to increase the vascular tone. Indeed, in physiological conditions, endothelial cells produce nitrous oxide (NO), which favors the relaxation of smooth cells (Tousoulis et al., 2012), whereas in the presence of oxysterols, NO is neutralized by O2 •− , giving peroxynitrite (ONOO− ), which can further trigger various cytotoxic effects (Lubos et al., 2008) on the cells of the vascular wall. Moreover, 7KC (as well as 7␣OHC and 7␤OHC), which are also found in high amounts in oxLDL (Brown and Jessup, 1999), can induce inflammation on human endothelial cells and increase expression of adhesion molecules (Lemaire et al., 1998), which could further contribute to the accumulation of monocytes at the sub-endothelial level (Stocker and Keaney, 2004). In oxysterol-induced cytokinic inflammation, the central role played by PKC␦ and by the ERK1/2 pathway, associated with Ca2+ influx, was demonstrated (Prunet et al., 2006a; Lemaire-Ewing et al., 2009; Leonarduzzi et al., 2010). As 7KC favors monocytic differentiation and foam cell formation in vitro (Hayden et al., 2002) and potentiates pro-inflammatory molecule production by M1 (pro-infammatory) and M2 (anti-inflammatory) macrophage subsets (Buttari et al., 2013), this oxysterol could contribute to fatty streak formation, the first step of atherosclerotic plaque formation, characterized by the sub-endothelial accumulation of monocytes, and the intracellular accumulation of lipid in these cells (foam cell formation) (Vejux and Lizard, 2009). The ability of 7KC to induce phospholipidosis could also favor lipid accumulation into the cells of the vascular wall (Schmitz and Müller, 1991; Schmitz and Grandl, 2008; Vejux et al., 2009). Atherosclerotic plaque progression can be also at least in part under the control of 7KC. Indeed, as this oxysterol triggers the production of angiogenic factors by macrophages (Buttari et al., 2013), this event can have important impacts to vasa vasorum angiogenesis and subsequently

on plaque growth (Slevin et al., 2009). High circulating levels of 7␤OHC and 7␣OHC were also found in normocholesterolemic atherosclerotic patients undergoing endarterectomy (Prunet et al., 2006b). They were associated with the presence of apoptotic and oxidative markers in atherosclerotic lesions suggesting that 7␤OHC and 7␣OHC could be more appropriate biomarkers of lipid metabolism disorders than cholesterol or LDL in normocholesterolemic patients with atherosclerosis of the lower limbs (Prunet et al., 2006b). In advanced atherosclerotic lesions, several oxysterols also contribute to plaque erosion and rupture. Thus, cholestane-3beta,5alpha,6beta-triol has been shown to promote vascular smooth muscle cells calcification which is known to weaken the arterial wall (Liu et al., 2004). Among the processes which can contribute at least in part to atherosclerotic plaque instability, the potential impact of oxysterols on metalloproteases has also received increasing attention. In human monocytic U937 cells, an oxysterol mixture of a composition similar to that found in advanced human carotid plaques has been shown to trigger MMP-9 gene and protein expression through the induction of NADPHoxidase (Nox2) activity which causes ROS production (Gargiulo et al., 2011). However, this oxysterol mixture did not modify the levels of the tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-2 (Gargiulo et al., 2011). As studies have further elucidated the roles of oxysterols (especially 7␣,25-dihydroxycholesterol, also called 5cholesten-3␤,7␣,25-triol, and 25-OHC) in controlling the functions of cells of the innate and adaptive immune systems through transcription factors such as the liver X receptors (LXRs), sterol regulatory element-binding proteins (SREBPs) and the G protein-coupled receptor EBI2, and in regulation of the differentiation, migration and population expansion of immune cells (Hannedouche et al., 2011; Spann and Glass, 2013; Daugvilaite et al., 2014), evidence supports that oxysterols other than those resulting from autoxidation could also be involved in the atherosclerotic process. Moreover, under treatment with different oxysterols, especially those inducing cell death (Lemaire-Ewing et al., 2005), an overproduction of ROS, attributed to NADPH-oxidase activity, with a disruption of RedOx homeostasis has been observed on the different cell types of the vascular wall such as endothelial cells, smooth muscle cells and macrophages (Yuan et al., 2000; Pedruzzi et al., 2004; Li et al., 2011). It is therefore tempting to speculate, that oxysterol-induced side effects are probably involved in the different steps of the atherosclerotic process and that the ability of oxysterols to perturb lipid homeostasis via phospholipidosis (Vejux et al., 2005; Schmitz and Grandl, 2009), leading to a complex mode of cell death involving an overproduction of reactive oxygen species, apoptosis and autophagy (termed “oxyapoptophagy”) (Monier et al., 2003; Nury et al., 2014) is likely to play an important role in atherosclerotic plaque development and instability (Jia et al., 2007). Thus, while the multifactorial genesis of arteriosclerosis cannot be dismissed, there are currently a number of theories supporting that several oxysterols can contribute to arterial dysfunctions associated with ageing. To date, the most powerful molecule capable of counteracting oxysterol induced-side effects (especially 7KC and 7␤OHC present at elevated level in oxLDL and in atheromatous plaque), is vitamin E (alpha-tocopherol) (Vejux and Lizard, 2009). However, the ability to inhibit the side effects of oxysterols by the inactivation of NADPH-oxidase supports that this enzyme could also constitute a suitable target for the prevention of oxysterolinduced atherosclerosis (Pedruzzi et al., 2004; Leonarduzzi et al., Q4 2006). 3.2. Type 2 diabetes mellitus In the elderly hypercholesterolemia and increased lipid peroxidation contribute to increased oxysterol formation which favors development of cardiovascular diseases and could trigger type 2


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diabetes mellitus, a complex disease that involves insulin secretion abnormalities and defects in the action of insulin on its target tissues (Boitard, 2002; Negre-Salvayre et al., 2010) The involvement of a disruptionof RedOx homeostasis in diabetic patients and in diabetic rat hearts is supported by increased levels of 7␤OHC, 7␣OHC and 7KC which could constitute suitable biomarkers of oxidative stress and of lipid peroxidation in diabetes (Matsui et al., ˜ et al., 2011). To date, although few stud1997; Menéndez-Carreno ies indicate that oxysterols contribute to the development of type 2 diabetes, it is tempting to speculate that some oxysterols, especially those resulting from lipid peroxidation, may play a role in the development of this disease (Vaya et al., 2011). Indeed, proflin-1, which is increased in the diabetic endothelium, is up-regulated by 7KC via oxysterol binding protein 1 (OSBP1) (Romeo and Kazlauskas, 2008). Moreover, LXR activation inhibits hepatic gluconeogenesis and lowers serum glucose levels, indicating a possible application for LXR activation in the treatment of diabetes (Geyeregger et al., 2006). In addition, in the insulinoma cell line MIN6, which is derived from a transgenic mouse expressing the large T-antigen of SV40 in pancreatic beta cells, various effects of 7KC have been observed including a decrease of insulin secretion into the culture medium (Boumhras, 2012).

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3.3. Alzheimer’s disease

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Alzheimer’s disease (AD) is the most common form of dementia. This disease is characterized by the formation of protein aggregates in the human brain, extracellular deposition of A␤ in senile plaques and intracellular accumulation of hyperphosphorylated Tau (Tubulin Associated Unit) in neurofibrillary tangles (NFT) (Blennow et al., 2006). Neuron degeneration and synaptic loss are two additional histological characteristics of AD which are associated with clinical symptoms related to cognitive impairment rather than NFT and A␤ deposition (Jack et al., 2009, 2010). Dysregulation of brain cholesterol homeostasis has been linked to AD. A strong genetic risk factor for late-onset AD is the presence of the ␧4 allele of the apolipoprotein E (APOE) gene, which encodes a protein (APOE4) with crucial roles in cholesterol metabolism. There is now mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of A␤ peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors (Bu, 2009). It is also well established that variations in the ApoE ␧4 allele are associated with the major pathological markers of AD such as A␤ deposition, Tau pathology and synaptic degeneration (Di Paolo and Kim, 2011). Whereas cholesterol homeostasis can be considered as an important factor in the pathogenesis of AD (Di Paolo and Kim, 2011) contradictory data have been reported both in vitro and in vivo. In vitro studies have generally demonstrated that increasing cholesterol levels in cultured cells results in enhanced amyloid precursor protein (APP) production and A␤ formation, and in the accumulation of phosphorylated Tau (Wood et al., 2014). When cellular cholesterol content was lowered, the non-amyloidogenic pathway was favored (increased ␣-secretase (ADAM10) activity) rather than the amyloidogenic pathway (reduced ␤-secretase (BACE1) activity and A␤ production) (Bodovitz and Klein, 1996; Simons et al., 1998). Paradoxally, in primary cultures of rat embryo hippocampal neurons, a moderate reduction of neuronal cholesterol results in increased ␤-secretase cleavage, associated with a spatial association of APP and ␤-secretase, and with enhanced A␤ processing (Abad-Rodriguez et al., 2004). As these data contradict previous work in which acute and drastic reduction of membrane cholesterol resulted in decreased amyloid production (Simons et al., 1998; Fassbender et al., 2001; Ehehalt et al., 2003), it was suggested that this difference might be due to higher amounts of APP in the lipid rafts of the cells used.

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Moreover, it has been established that the levels of APP, as well as that of ␤ and ␥ secretases contributing to its cleavage, are enriched in cholesterol-rich regions of the cytoplasmic cell membrane known as lipid rafts, which are believed to play important roles as platforms for the partitioning of transmembrane and synaptic proteins involved in synaptic signaling, plasticity, and maintenance (Burns and Duff, 2002; Ehehalt et al., 2003; Zonta and Minichiello, 2013). Low levels of membrane cholesterol decrease the accumulation of APP in the lipid rafts, and decrease the production and the secretion of A␤ (Simons et al., 1998; Fassbender et al., 2001; Ehehalt et al., 2003). In vivo, one of the first studies which established that cholesterol might contribute to the production of A␤, was realized in cholesterol rich feed rabbits (Sparks et al., 1994). A high amount of cholesterol in the diet was shown to induce neurological symptoms and cytological modifications evocating those observed in humans: impaired spatial memory, a significant loss of cholinergic neurons, increased levels of APP, A␤ and phosphorylated Tau in the cerebral cortex, as well as increased levels of neuronal ␤-secretase (Ghribi et al., 2006; Woodruff-Pak et al., 2007; Ehrlich and Humpel, 2012; Schreurs et al., 2013). In wild mice, (C57BL/6), a cholesterol rich fat diet favors a neuroinflammatory response in the brain (immunohistochemical analysis revealed the presence of activated microglia and astrocytes in the hippocampus) and cognitive dysfunctions (Thirumangalakudi et al., 2008). In transgenic mice used as model for amyloidogenesis, whereas most of the studies show that hypercholesterolemia contributes to increase cognitive dysfunctions, some others reveal that cholesterol rich fat diet had no effects or could even decrease AD pathogenesis (Maulik et al., 2013). It was supposed that such differences could depend on age, sex and on the type of mice considered. It is noteworthy, that in old rats it has been reported that constitutive hippocampal cholesterol loss underlies poor cognition (Martin et al., 2014). In humans, the enhancement of brain cholesterol levels during normal ageing and in neurodegenerative diseases is also controversial. The increased cholesterol may be explained as a consequence of myelin breakdown which releases cholesterol into the cerebrospinal fluid (CSF) and extracellular space leading to excess cholesterol levels and neuronal death (Bartzokis, 2011). This theory is plausible since myelin levels are reduced with ageing and are considerably reduced in mild cognitive impairment (MCI) and dementia. However, in postmortem studies, it was shown that cholesterol diminished linearly from 20 years of age in frontal and temporal cortices (Svennerholm et al., 1994) and in the white matter of AD patients (Roher et al., 2002). In addition, when white matter cholesterol was examined as a function of age, a continuous decline occurred with increasing age in the control cohort (Roher et al., 2002). Lower cholesterol levels were explained as a consequence in cholesterol synthesis deficiency or as a cholesterol depletion resulting from a shift of cholesterol to gray matter. It was also reported that the amount of cholesterol in brain was highly variable during aging, ranging from no change to a 40% decrease (Söderberg et al., 1990). Approximately 25% of cholesterol is localized in the central nervous system in humans, especially in myelin (70%), mainly in its non-esterified form Björkhem and Meaney (2004). In adults, brain cholesterol is synthesized in situ (Björkhem, 2006). The excess of cholesterol is eliminated after conversion in 24S-OHC (also named cerebrosterol) which has been discovered in 1953 (Di Frisco et al., 1953). Indeed, as brain cholesterol is not able to freely cross the blood brain barrier, its major exportable form is 24S-OHC generated by the cholesterol 24-hydroxylase (CYP46A1) (Björkhem and Meaney, 2004). In the brain, CYP46A1 expression is restricted to neurons (Lund et al., 1999), and localized in the endoplasmic reticulum (Mast et al., 2008). It has been reported that the level of this enzyme increases with age, and that this change could contribute


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to the cognitive decay in the old age (Lund et al., 1999; Martin et al., 2008). Currently, numerous data support that 24S-OHC could play important roles in ageing and neurodegeneration. 24S-OHC, the primary metabolite of brain cholesterol was measured in the CSF and plasma of elderly and demented subjects by several research groups. Results of these studies reported that in the absence of neurodegeneration, plasma levels of 24S-OHC, which are stable during the first six decades of life, begin to diminish with age in parallel with a decline in total brain volume (Fotenos and Snyder, 2005; Björkhem, 2006). 24S-OHC reduction was found to be negatively correlated with the severity of dementia and the degree of brain atrophy in AD patients (Bretillon et al., 2000; Papassotiropoulos et al., 2000; Solomon et al., 2009). Thus, higher concentrations of this oxysterol have been found in the early stages of cognitive impairment and lower concentrations in more advanced stages of AD when compared to cognitively normal controls. As plasma levels of 24S-OHC result from the balance between brain-secretion capacity and liver-metabolic and clearance capacity, level disturbances of this oxysterol within the plasma of AD patients may reflect damage in their brains. In fact, enhanced 24SOHC plasma levels during the first stages of dementia have been explained as a consequence of a higher turnover of plasma membranes and myelin destruction, due to neuronal damage, thereby providing higher levels of cholesterol to be converted into 24S-OHC (Lütjohann et al., 2000; Zuliani et al., 2011). Furthermore, studies of brain atrophy showed that plasma 24S-OHC is associated with total brain volume and especially in the brain regions responsible for cognitive functions, i.e.: the hippocampal volume, the gray matter and the ventricle volumes (Koschack et al., 2009; Solomon et al., 2009). This supports the theory that 24S-OHC acts as a marker of metabolically active neurons in the brain (Leoni and Caccia, 2011). Bogdanovic et al. noted an induction of CYP46A1 expression in astrocytes of AD patients, but not in controls (Bogdanovic et al., 2001). In addition, a lower CYP46A1 expression in neurons of AD brains was associated with a higher CYP46A1 activity in astrocytes (Kriˇstofiková et al., 2012). This abnormal expression in astrocytes was proposed to be a compensatory mechanism of cholesterol metabolism due to disturbances in degenerating neurons. CYP46A1 was also detected in the neuritic periphery of plaques (Brown et al., 2004). Noteworthy, it has been reported that the levels of this enzyme increase with age. Indeed, two fold increases in the expression of CYP46A1 was reported in hippocampal neurons at different stages of development (Martin et al., 2008). Genetic polymorphisms of CYP46A1 alter 24S-OHC production and are associated with a higher risk of late-onset sporadic AD, an increased A␤ load in brain tissues, as well as an increased CSF level of A␤ and phosphorylated tau protein (Papassotiropoulos et al., 2003; Garcia et al., 2009). In fact, some evidence suggests that 24S-OHC inhibits A␤ production by modulating expression of genes coding APP and ␤secretase and stimulating the non-amyloidogenic pathway. A net increase in sAPP␣ secretion as well as a significant doubling of ␣secretase and down-regulation of ␤-secretase activities occurred in SH-SY5Y cells treated with 24S-OHC (Famer et al., 2007; Prasanthi et al., 2009). In addition, a significant up-regulation of the APP level was observed in primary cultures consisting of almost equal populations of human neuronal and glial cells, after treatment with 10 ␮M of 24S-OHC (Alexandrov et al., 2005). Levels of another oxysterol of enzymatic origin, 27-OHC, the most abundant oxysterol in the human circulation (Khatib and Vaya, 2014), were increased in the frontal cortex of patients with AD versus control individuals (Heverin et al., 2004). CYP27A1 expression and plasmatic 27-OHC levels were decreased in AD patients (Brown et al., 2004; Kolsch et al., 2004). Treatment of SH-SY5Y cells with 5–15 ␮M of 27-OHC showed that this oxysterol significantly up-regulated APP levels and ␤-secretase activity (Prasanthi et al., 2009). Recently, Gamba et al. (2014) showed an increase

in both 27-OHC and 24S-OHC in the frontal cortex of AD brains with a trend that appears related to the disease severity. Differentiated human neuroblastoma SK-N-BE cells exposed to 27-OHC and 24S-OHC, at concentrations detected in AD and normal brain, demonstrated an up-regulation of APP, ␤-secretase expression and ␤-secretase activity, as well as a marked production of A␤1–42. The addition of 27-OHC to primary human neuron cells significantly reduced A␤ in cell culture supernatants without affecting ␣-, ␤- or ␥-secretase activity but by inducing neuronal ABCA1, ABCG1 and ApoE expression which indicates that this oxysterol may contribute to the regulation of pathways involved in AD due to its action as an LXR ligand (Kim et al., 2009). The implication of other oxysterols in the pathogenesis of AD and in particular their eventual capacity to induce A␤ aggregation has been investigated. Indeed, 7KC and 7␤-OHC, resulting from cholesterol autoxidation (Iuliano, 2011) and which could be formed as a consequence of the oxidative stress often observed in AD (Vaya and Schipper, 2007), were shown to enhance A␤ insertion into the lipid bilayer by decreasing intermolecular cohesive interaction (Kim and Frangos, 2008). Recently, Phan et al. (2013) used model membranes to investigate the localization of A␤ in membranes and peptide-induced membrane dynamics in the presence of 7KC or 25-OHC. They demonstrated that 7KC significantly facilitated A␤ localization in these membranes, while 25-OHC stimulated its insertion and induced membrane transformation. Interestingly, 7KC-induced cytotoxicity on neuronal cells is counteracted by 24SOHC via transcriptional activation of the LXR signaling pathway (Okabe et al., 2013). In addition to ␤-amyloid (A␤) and tau protein, a diverse number of factors such as cardiovascular risk factors (inflammation, lipid metabolism disorders) may also play significant roles in vascular dementia, corresponding to the vascular forms of AD (Fiolaki et al., 2014). Vascular injuries are widely suspected to contribute to cognitive decline in ageing (Marchant et al., 2013). Elevated blood pressure has also been associated with an increased risk of white matter lesions (Vuorinen et al., 2011) and the progressive deterioration of cholesterol homeostasis appears to have a central role (Leduc et al., 2010). It has also been reported that an elevated cerebral A␤ level was associated with low-density lipoprotein cholesterol in a pattern analogous to that found in coronary artery disease (Reed et al., 2014). Moreover, there is evidence of an inter-relationship between oxysterols and ATP-binding cassette transporters (Ruiz et al., 2013; Wang et al., 2013), (especially ABCB1 (P-glycoprotein, P-gp) expressed by endothelial cells), which are not only involved in cholesterol homeostasis, but which also participate in the clearance of A␤ from the brain to the blood stream (Abuznait and Kaddoumi, 2012). Therefore, major risk factors associated with AD can be correlated with oxysterol-induced vascular damage, and the contribution of oxysterols to the vascular form of AD (vascular dementia) can be assumed. Therefore, there is strong evidence in support of the involvement of oxysterols (especially 24S-OHC, 27-OHC, 7KC and 7␤OHC) in AD (Table 1). So, the development of treatments raised against the side effects triggered by these oxysterols are of interest. To prevent oxysterol-induced neurodegeneration, conventional therapeutic approaches using anti-oxidant molecules, such as N-acetyl cysteine could be used (Gamba et al., 2014) as well as metalloproteinases and metalloproteinase inhibitors (Gargiulo et al., 2014). In addition, innovative therapeutic approaches are also very promising. Nanoparticles loaded with quercetin, which has demonstrated the ability to counteract oxysterol-induced neuroinflammation, have been investigated (Testa et al., 2014). Moreover, as the catabolic pathway of cholesterol leading to the formation of 24S-OHC via CYP46A1 is a serious therapeutic target, gene therapy could be used. Indeed, injection of adeno-associated vector (AAV) encoding CYP46A1 in the cortex and hippocampus of APP23 mice,


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Table 1 Effects of oxysterols on APP processing and membrane characteristics. Oxysterols

Experimental models

Oxysterols effects (APP processing, cytoplasmic membrane transporters, membrane dynamic)

References

24S-OHC and 27-OHC

Human neuroblastoma SH-SY5Y cells

Famer et al. (2007)

24S-OHC and 27-OHC

Human neuroblastoma SH-SY5Y cells

24S-OHC 24S-OHC and 27-OHC

Human neural cells primary culture (HN cells) Differentiated human neuroblastoma SK-N-BE cells

27-OHC

HN cells

7KC and 7␤OHC

Lipid membranes

7KC and 25-OHC

Liposomes

With 24S-OHC − Increase sAPP␣ secretion − Increase ␣-secretase activity − Decrease ␤-secretase (BACE1) activity − Increase of intra- and extracellular level of sAPP and sAPP␣ With 27-OHC: no significant effects With 24S-OHC − Increase of extracellular sAPP␣ levels With 27-OHC − Increase of A␤1–42 levels − Increase of APP levels − Increase of ␣-secretase (ADAM10) activity 24S-OHC + 27-OHC − No significant changes in A␤1–42 levels − Increase of ␣-secretase activity − Upregulation of A␤ With 24S-OHC − Overexpression of APP − Increase of ␣-secretase expression/activity − Increase of ␣-secretase expression/activity − Increase of A␤1–42 production With 27-OHC − Increase of of ␤-secretase expression/activity − Increase of ␣-secretase expression/activity − Increase of ␥-secretase activity − Increase of A␤1–42 production − Significant reduction of A␤ peptide level in the culture medium − No effect on ␣-, ␤- or ␥-secretase activities − Increase in ABCA1, ABCG1 and ApoE mRNA and protein levels With 7KC and 7␤OHC − Substitution of membrane cholesterol with 7KC and 7␤OHC With 7KC and 25-OHC − Higher absorption of A␤ in membranes enriched in 7KC − Higher effect of 25-OHC on A␤-induced membrane fluctuation − 25-OHC facilitates A␤ accumulation in the membrane

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before the onset of amyloid deposits, markedly reduced A␤ peptides, amyloid deposits and trimeric oligomers at 12 months of age (Hudry et al., 2010). The Morris water maze procedure also demonstrated an improvement in the spatial memory of mice at 6 months, before the onset of amyloid deposits (Hudry et al., 2010). AAV5-wtCYP46A1 vector injection in the cortex and hippocampus of amyloid precursor protein/presenilin 1 (APP/PS1) mice after the onset of amyloid deposits also markedly reduced the number of amyloid plaques in the hippocampus, and to a lesser extent in the cortex, 3 months after the injection (Hudry et al., 2010).

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3.4. Age-related macular degeneration

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Age-related macular degeneration (AMD) is characterized by irreversible vision loss (abolished central vision) and blindness, with a targeting of the choroid, retinal pigment epithelium (RPE) and retina. In AMD, abnormal lipoprotein deposits are located in Bruch’s membrane where they are called “drusen” when in linear form and “focal basal deposits” when in diffuse form. Drusen-contains-esterified and unesterified-cholesterol as well as oxysterols (Rudolf and Curcio, 2009; Curcio et al., 2005; Javitt and Javitt, 2009). Chronic inflammation, oxidative stress and cell death are suspected to play a role in the pathogenesis of AMD. The presence of drusen is associated with oxidative stress, apoptosis and accumulation of A␤ peptide (Ding et al., 2009; Dentchev et al., 2003). Several studies have suggested a link between cholesterol

Prasanthi et al. (2009)

Alexandrov et al. (2005) Gamba et al. (2014)

Kim et al. (2009)

Kim and Frangos (2008)

Phan et al. (2013)

metabolism, especially the conversion of cholesterol to oxysterols, and retinal degeneration. Indeed, a cholesterol-enriched diet fed to rabbits for 12 weeks induced increased levels of A␤, oxidative damage, apoptotic cell death and an accumulation of cholesterol and oxysterols (27-OHC, 24S-OHC, 22-hydroxycholesterol, 7␣OHC, 4␤-hydroxycholesterol, and 25-OHC) in the retina (Dasari et al., 2011). In a previous study, this team demonstrated that 27-OHC caused toxicity in RPE cells by inducing an increase in A␤1–42 peptide production and ER stress specific markers (caspase 12 and CHOP); a reduction in mitochondrial membrane potential; Ca2+ dyshomeostasis; oxidative stress (glutathione depletion, ROS generation); inflammation and apoptosis (Dasari et al., 2010). Cholesterol metabolism and its oxidized products like 7KC have also been shown to adversely impact retinal pigment epithelium cells (Sharma et al., 2014). Thus, 7KC was involved in the induction of oxidative stress and cell death. Different modifications were observed in the retinal pigment epithelial cells exposed to 7KC, i.e: damage to the full-length intact mtDNA, mitochondrial dysfunction, an increase in ROS/RNS production (Gramajo et al., 2010) and caspase-8, -12, -3 activation (Neekhra et al., 2007; Luthra et al., 2006). 7␤OHC induced a caspase-3-independent mode of cell death in association with lysosomal destabilization in ARPE-19, human retinal pigment epithelial cells (Malvitte et al., 2008). Oxysterols may also be responsible for the inflammation associated with AMD (Joffre et al., 2007). Indeed, in retinal cells, oxysterols induced an increase of inflammatory cytokines. In ARPE-19 cells,


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25-OHC (20–30 ␮g/mL) stimulated IL-8 (involving MEK/ERK1/2 pathway), MCP-1 and VEGF secretion (Dugas et al., 2010). Transcription and secretion of IL-8 were increased after treatment with 25-OHC through a mechanism that is dependent on ERK1/2 and PI3K activity and involving the transcription factors, NF-␬B and AP-1 (Catarino et al., 2012). 7KC and 7␤OHC induced an increase in IL-6 and IL-1␤ secretion, respectively, in ARPE-19 cells (Dugas et al., 2010). Huang et al. (2012) also demonstrated that 7KC (8 ␮M) increased the expression of IL-6, VEGF, IL-1␤, IL-8, TNF-␣ and TGF-␤1 mRNA and secreted protein levels in a mechanism which probably involved ER stress. Another team demonstrated that cytokine production was induced by 7KC via three kinase signaling pathways, AKT-PKC␨-NF␬B, p38 MAPK, and ERK through interactions in the plasma membrane (Larrayoz et al., 2010). The MAPK/ERK pathways were associated with the activation of NF␬B (Larrayoz et al., 2010). In the context of AMD, resveratrol has demonstrated some protective effects against oxysterol-induced cell death and VEGF secretion and this polyphenol could be valuable in AMD treatment (Dugas et al., 2010).

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3.5. Cataract

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Cataract, which is a term referring to the clouding of the eye’s natural lens, is the dominant cause of blindness worldwide (Vrensen, 2009). As early as the fourth or fifth decade of life this disease develops in the crystalline lens of the eye or in its envelope, resulting in slight to complete opacity and thereby obstructing the passage of light. Cataract is characterized by various symptoms: blurred vision, glare, halos, dull colors and cloudy vision. Cataract formation is described as a multi-factorial disease associated with smoking, diabetes, and excessive exposure to sunlight, all of which are known to induce oxidative stress (Vrensen, 2009). Currently, the most frequent and efficient treatment for cataract is surgical intervention to restore vision in patients. The first description of a possible involvement of lipids in human cataract is based on the discovery of lipoidal material in the crystalline lens and reported by Berzelius in 1825 (Berzelius, 1825–1831). Feldman and Feldman (1965) demonstrated that cholesterol is constitutively present in large amounts in the normal lens. When comparing normal lens with cataractous human lens, higher amounts of cholesterol, cephalins, lecithin and sphingomyelin were observed in the latter (Feldman and Feldman, 1965). Therefore, repartition of cholesterol, which represents approximately 40% of the total lipids of human lens fibers (Zigman et al., 1984) or modification of cholesterol levels by intrinsic or extrinsic factors may alter optical lens properties. Indeed, in various pathologies associated with defects in cholesterol metabolism patients develop cataract, as in the case of Smith–Lemli–Opitz syndrome, mevalonic aciduria or cerebrotendinous xanthomatosis which are characterized by mutations in the enzymes of cholesterol metabolism (7-dehydrocholesterol reductase, mevanolate kinase, and CYP27A1, respectively) (Cenedella, 1996). Moreover, with regards to oxidative damage, the lipid lens composition is devoid of oxidizable polyunsaturated fatty acids but has a high content of dihydrosphingomyelin (less prone to oxidation), this particular lipid composition favors cholesterol autoxidation. As the human lens membrane contains the highest cholesterol levels of any known biological membrane and is continuously in a strong photoxidative environment, a chronic exposure to UV light and ozone can lead to the formation of certain oxysterols (Wentworth et al., 2003; Vejux and Lizard, 2009; Brian and Taylor, 2001; Smith, 1987; Pulfer et al., 2005; Dreyfus et al., 2005). These oxysterols may contribute to the disruption of cholesterol repartition and homeostasis in human lens fibers. In human cataracts obtained by routine extracellular surgery, the oxysterols, 7␤OHC,

7KC, 5␣,6␣-epoxycholestanol, 20␣-hydroxycholesterol, and 25OHC, were identified by gas chromatography (Girão et al., 1998). No detectable amounts of cholesterol oxides were present in clear lens (Girão et al., 1998) which suggests that oxysterols may be involved in cataract development. Moreoever, 7KC might constitute an important risk factor in the physiopathology of cataract. This oxysterol may change Na/K ATPase activity (Duran et al., 2010) and intracellular lipid homeostasis (Vejux et al., 2005), two parameters which are implicated in the functioning of the lens. Na/K ATPase activity is fundamental to the maintenance of ionic concentration gradients and transparency of the lens (Lichtstein et al., 2000) and an altered lipid composition modifies lens membrane fluidity (McGowan et al., 1999). In addition, as some oxysterols are known to interact with cellular membranes (Royer et al., 2009; Wang and Megha London, 2004; Mintzer et al., 2010) and to induce changes in cholesterol and phospholipid content (Vejux et al., 2005), they could also modify the distribution of cholesterol in human lens fibers thereby contributing to lens opacity (Rujoi et al., 2003). All of these studies suggest the involvement of oxysterols in the development of cataracts but a better understanding of the mechanisms induced by oxysterols in the physiopathology of cataract is required in order to attempt to develop if not curative, at least preventive treatments. 3.6. Osteoporosis Osteoporosis is characterized by an excessive fragility of the skeleton, due to decreased bone mass and deterioration of bone microarchitecture. The disease is characterized by a decrease in bone density and quality leading to an increased risk of fragility fractures, especially of the hip, spine and wrist. The strength of the bones is the result of a delicate balance between two types of bone cells: osteoblasts, which strengthen the bone, and osteoclasts (responsible for bone resorption), which weaken them. Currently, several studies have reported that oxysterols can stimulate the differentiation of osteoblasts (Aghaloo et al., 2007; Richardson et al., 2007). In osteogenesis, 20(S)-hydroxycholesterol, alone or in association with 22(S)- or 22(R)-hydroxycholesterol, has important beneficial activities and is a potent modulator of critical signaling pathways capable of preventing osteoporosis. Thus, 20(S)-hydroxycholesterol, whether or not it is associated with 22(S)- or 22(R)-hydroxycholesterol, is a strong inducer of osteogenic differentiation (Kha et al., 2004). The osteogenic effects of these oxysterols were mediated via cyclooxygenase (COX)/phospholipase A2 (PLA2)- and mitogen activated protein kinase (MAPK)-dependent mechanisms (Kha et al., 2004). These oxysterols also induce osteogenic differentiation through activation of the hedgehog signaling pathway (Kim et al., 2007; Richardson et al., 2007) and they are also capable of activating the Wnt-related signaling pathway, thereby playing a role in the regulation of the proliferation and differentiation of osteoblasts during bone formation (Johnson et al., 2004; Hu et al., 2005; Amantea et al., 2008). However, cholestan-3␤,5␣,6␤-triol can inhibit osteoblastic differentiation and promotes apoptosis of rat bone marrow cells (Liu et al., 2005), suggesting that some oxysterols may contribute to osteoporosis, a degenerative disease of the skeleton caused by an alteration in bone turnover homeostasis and resulting in an increased susceptibility to bone fractures (Riggs and Melton, 1992). In agreement with this hypothesis, elevation of 27-OHC, either pharmacologically (by injection) or by genetically disrupting the CYP7B1−/− locus (the enzyme responsible for the catabolism of 27-OHC), resulted in significantly decreased trabecular and cortical bone (DuSell et al., 2010). Importantly, in the CYP7B1−/− mouse model the effects of 27-OHC on bone were partially reversed by administering pharmacological doses of 17-␤ estradiol, a result which implicates estrogen receptors as one target of the


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pathological actions of 27-OHC. In this study, it was also observed that while ovariectomy alone had minimal effects on cortical bone in wild type mice, a dramatic loss of bone was observed in ovariectomized mice in which 27-OHC levels were elevated. By extrapolation, this latter finding suggests that post-menopausal women with elevated cholesterol, and consequently elevated 27-OHC, may be at increased risk for cortical fractures (Nelson et al., 2013). It is therefore of interest to assess the impact of specific CYP27A1 inhibitors on bone biology and determine the potential utility of this approach to mitigate the impact of hypercholesterolemia on bone.

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3.7. Age related cancers: Colonic and prostatic cancers

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The cancer ageing hypothesis suggests that altered age promoting activities such as regulation of tumor suppressor mechanisms leading to DNA damage can play important roles in neoplasic progression (Liu and Sharpless, 2009). Beside genetic factors, long term exposure to environmental factors (brought by diet, or endogeneously formed by oxidative stress resulting from a disruption of RedOx homeostasia), which increases with age, also favors the hypothesis that some oxysterols (especially those resulting from autoxidation) (Smith et al., 1979; Jusakul et al., 2011) could play critical roles in age-related carcinogenesis, especially in prostatic cancer in men, and in colonic cancer in men and women. Noteworthy, in contrast to oxysterols, plant sterols (including phytosterols) may have potential beneficial effects including anti-inflammatory, anti-oxidant and anti-cancer activities (Rudkowska, 2010). Naturally air-aged commercial samples of cholesterol have been described to induce mutagenicity using the Ames test (Smith et al., 1979). Furthermore, the genotoxic properties of various oxysterols including cholesterol-3␤, 5␣,6␤-triol, and cholesterol5␣-6␣-epoxide have been confirmed in different animal and human cell types (Jusakul et al., 2011). Many oxysterols, such as cholesterol-3␤, 5␣,6␤-triol, 7KC and 7␤OHC, found in appreciable amounts in powdered milk, cheese, egg products and some other industrial processed foods, are potent inducers of oxidative stress which can contribute to DNA damage (chromosome aberrations, 8-oxoguanine formation) leading to carcinogenesis (Cheng et al., 2005; Monier et al., 2003). Therefore, during ageing which is associated with a lower efficiency of DNA repair, it cannot be dismissed that certain oxysterols may promote the development of tumors. It has been suggested that pro-carcinogenic oxysterols might exert their effect at three stages of carcinogenesis: by induction of DNA damage; by enhancing production of cyclooxygenase-2 (COX-2) and by stimulation of tumor cell migration (Silva et al., 2003; Yoon et al., 2004; Jusakul et al., 2011). There is substantial evidence to support the involvement of oxysterols in two major age-related cancers (colonic and prostatic cancers). Animal fat oxidation products, including oxysterols, have been linked to colon carcinogenesis (Jusakul et al., 2011). In addition, patients with ulcerative colitis, a condition with an increased risk for developing colon cancer, excrete high levels of cholesterol, coprostanol and cholestane-3␤-5␣-6␤ triol in feces compared to patients with other digestive diseases and healthy controls (Reddy et al., 1997). However, the carcinogenic effect of oxysterols has not been demonstrated in rat colons. Indeed, no colonic tumors were induced by sterols including cholesterol epoxide, cholestanetriol and cholesterol in standard and germ free female rats (Reddy and Watanabe, 1979). It is now established that colorectal cancers are sensitive to LXR activation which can be activated by various oxysterols and which are members of the nuclear receptor family that regulates intracellular lipid homeostasis (De Boussac et al., 2013a). Several studies support the concept that lipid metabolism plays a complex role in prostate cancer, the most frequent cancer associated with age in men. Thus, increased de novo synthesis of fatty acids and/or cholesterol is associated with the development of

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prostate tumors (Hoang et al., 2013; Dufour et al., 2012). A number of studies, going back many years, demonstrate that cholesterol accumulates in solid tumors and that cholesterol homeostasis breaks down in the prostate with aging and with the transition to the malignant state (Freeman and Solomon, 2004). There is now evidence that cholesterol metabolites can promote or suppress cancer (Silvente-Poirot and Poirot, 2014). In prostate cancer, LXRs activation has been shown to reduce the potential pathogenicity by reducing the accumulation of cholesterol via overexpression of ATP-binding cassette (ABC) transporters, especially ABCA1 and ABCG1, which are responsible for the export of endogenous cholesterol (De Boussac et al., 2013b). LXRs activation can also contribute to a decrease in the phosphorylation of Akt, a key player in the mechanism of cell survival and which can induce apoptosis in tumor cells (Pommier et al., 2010). Moreover, LXRs can also downregulate the accumulation of inflammatory molecules such as iNOS, COX-2 and IL-6, known to contribute to carcinogenesis (Joseph et al., 2003). Therefore, LXRs activation via endogenous oxysterols (resulting from cholesterol metabolism) or pharmacological LXRs ligands may limit the development of prostate cancer. Altogether, these data support that the targeting of the transcriptional activity of LXRs and consequently cholesterol/oxysterol metabolism can contribute to an amelioration in the progression of prostate cancer (De Boussac et al., 2013b). 4. Impact of oxysterols on the ageing process The involvement of oxysterols in the ageing process is still speculative, but several in vitro studies support a potential role for these compounds in ageing. It is proposed that their contribution to ageing could be the consequence either of a disruption of RedOx homeostasis which often occurs during ageing (Terlecky et al., 2006; Titorenko and Terlecky, 2011) and/or of altered cholesterol metabolism (Smiljanic et al., 2013; Fiorenza et al., 2013). The role of lipid peroxidation and consequently of lipid peroxidation products in the pathophysiology of ageing, and classically linked diseases, especially neurodegenerative diseases, diabetes and atherosclerosis, is widely suspected (Negre-Salvayre et al., 2010). Among these lipid peroxidation products, it is now well accepted that some oxysterols, especially those oxidized at C7, such as 7KC and 7␤OHC, can be cytotoxic (Lemaire-Ewing et al., 2005; Vejux and Lizard, 2009). Therefore, these oxysterols could constitute second messengers in the ageing process, and lead to various cell dysfunctions. In vitro, their cytotoxicity evaluated by their 50% inhibiting concentrations (IC50) values, is in the range of 25–50 ␮M in different types of cells: monocytic cells, bone marrow cells, vascular cells, retinal epithelial cells, colonic epithelial cells, and neuronal cells (Lizard et al., 1996; Ragot et al., 2013; Nury et al., 2013). These IC50 values are 500 to 1000 times higher than in the plasma of aged subjects or of hypercholesterolemic patients (Prunet et al., 2006b; Helmschrodt et al., 2013). It is however important to consider that oxysterol concentrations normalized to cholesterol were about 43 times higher in carotid plaque compared to plasma (Helmschrodt et al., 2013). Moreover, when 7KC and 7␤OHC are used at concentrations in the range of IC50 values, which are concentrations commonly used in toxicological studies in order to permit comparisons from one compound to another, only 10–35% accumulate within the cell (Miguet et al., 2001; Kahn et al., 2006). Interestingly, similar observations were performed with 27-OHC (Vurusaner et al., 2014). Based on these different considerations, it can be supposed that the intracellular oxysterol content obtained in vitro could be in the range of order of those occurring in vivo, whereas it must be also taken into account that important variabilities can occur inside a tissue from one cell type to another. So, it is noteworthy, that in the range of IC50 values, 7KCand 7␤OHC-induced cytotoxic effects are associated with a more


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Fig. 3. Contribution of oxysterols to the ageing process. Based on the biological activities of oxysterols, it has been proposed that their contribution to ageing could be the consequence either of a dysfunction of RedOx homeostasis which is often disrupted during ageing and/or of altered cholesterol metabolism. The trigger toward oxysterol-associated ageing processes and age-related diseases might depend on genetics, environmental conditions, and life-style.

or less marked induction of oxidative stress, cytokine secretion, and/or cell death (involving an apoptotic process which can be associated with autophagy: oxiapoptophagy) (Vejux and Lizard, 2009; 859 He et al., 2013; Nury et al., 2014) which are all hallmarks of the age860 ing process (Jenny, 2012; Liochev, 2013; López-Otín et al., 2013). 861 In addition, 7KC and 7␤OHC have a strong impact on mitochon862 drial activity and this effect could contribute to cell degeneration. 863 By analogy with neurodegenerative diseases, it is suggested that 864 this mitochondrial dysfunction could be, at least in part, due to 865 an excess of ROS production, which in turn favors alteration, by 866 carbonylation, of major enzymes involved in oxidative phosphor867 ylation (Galea et al., 2012), and consequently contributes to an 868 impairment of mitochondrial metabolism and bioenergetic failure 869 which is at the core of several age-related diseases. Moreover, 7KC 870 and 7␤OHC-induced mitochondrial depolarization has been shown 871 to be involved in PDK1/PKB (Akt)/GSK3 metabolic pathways (Ragot 872 et al., 2011; Ragot et al., 2013) which is often disturbed in age873 ing (Petit-Paitel, 2010) and in age-related diseases such as AD and 874 diabetes (Gao et al., 2011). 875 The involvement of oxysterols in ageing via dyfunctions of 876 cholesterol metabolism is mainly supported by data obtained in 877 patients with Alzheimer’s disease and age-related macular degen878 eration (Martin et al., 2010; Pikuleva and Curcio, 2014). Indeed, in 879 these diseases 24S-OHC probably plays an important role and it is 880 established that cholesterol 24S-hydroxylase (CYP46A1) converts 881 cholesterol into 24S-OHC in neurons and participates in cholesterol 882 homeostasis in the central nervous system, including the retina 883 Q5 (Björkhem, 2006, 2009; Fourgeux et al., 2014). During ageing, a low884 ered neuronal metabolism resulting from abnormal catabolism of 885 cholesterol into 24S-OHC cannot be excluded. 886 It is suggested that the trigger initiating oxysterol-associated 887 ageing processes and age-related diseases might depend on 888 genetic, environmental conditions, and on the differences in life889 style (Fig. 3). 890 857 858

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5. Conclusions Based on in vitro experiments, animal models and clinical studies, there is some evidence that several oxysterols resulting either from cholesterol autoxidation or enzymatic oxidation of

cholesterol are involved in age-related diseases and in ageing processes. Some organelles (mitochondria, lysosome, peroxisome), metabolic pathways (such as PI3-K/PDK-1/PKB (Akt)/GSK3, MEK/ERK and pathways), nuclear receptors (especially LXR), enzymes (such as NADPH-oxidases), associated with the biological activities of these compounds could constitute potential pharmacological targets (Pedruzzi et al., 2004; Lee et al., 2007; Lemaire-Ewing et al., 2009; Vejux and Lizard, 2009; Vejux et al., 2009; Ragot et al., 2011). However, a number of potential targets of oxysterols, such as sirtuins and length of telomeres which are involved in ageing (Min et al., 2013; Boccardi and Paolisso, 2014) still remain unexplored. In addition, whereas LXR receptors have been extensively studied, no information is available on the potential role of other oxysterol receptors: anti-oestrogen binding receptors (AEBS) (De Medina et al., 2011); oxysterol-binding protein (OSBP) (Olkkonen and Li, 2013); pregnan X receptor (Trousson et al., 2009); arylhydrocarbon receptor (Savouret et al., 2001), G protein-coupled receptor EBI2 (Gatto and Brink, 2013), and smoothened involved in the hedgehog signal transduction network (Robbins et al., 2012). In conclusion, whereas further investigations are required, there are currently numerous theories and experimental data supporting the notion that several oxysterols contribute to age-related diseases and are involved in ageing process. Therefore, a better knowledge of the biological activities of oxysterols should permit to improve the understanding of ageing process, and of the physiopathology of several age related diseases. Uncited references

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Javitt (2002). Acknowledgements This work was supported by grants from the Université Q7 de Bourgogne (Ecole Doctorale Environnements–Santé), Erasmus Q8 program (Université de Bourgogne, Dijon/University College of Cork (UCC), Cork), Campus France (ULYSSES program) and the French Embassy in Irlande via Dr Claude Detrez for his efficient support.


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References Abad-Rodriguez, J., Ledesma, M.D., Craessaerts, K., Perga, S., Medina, M., Delacourte, A., Dingwall, C., De Strooper, B., Dotti, C.G., 2004. Neuronal membrane cholesterol loss enhances amyloid peptide generation. J. Cell Biol. 167, 953–960. Abuznait, A.H., Kaddoumi, A., 2012. Role of ABC transporters in the pathogenesis of Alzheimer’s disease. ACS Chem. Neurosci. 3, 820–831. Aghaloo, T.L., Amantea, C.M., Cowan, C.M., Richardson, J.A., Wu, B.M., Parhami, F., Tetradis, S., 2007. Oxysterols enhance osteoblast differentiation in vitro and bone healing in vivo. J. Orthop. Res. 25, 1488–1497. Alexandrov, P., Cui, J.G., Zhao, Y., Lukiw, W.J., 2005. 24S-hydroxycholesterol induces inflammatory gene expression in primary human neural cells. NeuroReport 16, 909–913. Amantea, C.M., Kim, W.K., Meliton, V., Tetradis, S., Parhami, F., 2008. Oxysterolinduced osteogenic differentiation of marrow stromal cells is regulated by Dkk-1 inhibitable and PI3-kinase mediated signaling. J. Cell. Biochem. 105, 424–436. Bartzokis, G., 2011. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol. Aging 32, 1341–1371. Berzelius, J.J., 1825–1831. Lehrbuch der Chemie. Arnold, Dresden, pp. 525. Björkhem, I., Einarsson, K., Johansson, G., 1968. Formation and metabolism of 3-betahydroxycholest-5-en-7-one and cholest-5-ene-3-beta, 7-beta-diol Bile acids and steroids 192. Acta Chem. Scand. 22, 1594–1605. Björkhem, I., Lütjohann, D., Diczfalusy, U., Ståhle, L., Ahlborg, G., Wahren, J., 1998. Cholesterol homeostasis in human brain: turnover of 24Shydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J. Lipid Res. 39, 1594–1600. Björkhem, I., Meaney, S., 2004. Brain cholesterol: long secret life behind a barrier. Arterioscler. Thromb. Vasc. Biol. 24, 806–815. Björkhem, I., 2006. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J. Intern. Med. 260, 493–508. Björkhem, I., 2009. Are side-chain oxidized oxysterols regulators also in vivo? J. Lipid Res. 50, S213–S218. Blennow, K., De Leon, M.J., Zetterberg, H., 2006. Alzheimer’s disease. Lancet 368, 387–403. Boccardi, V., Paolisso, G., 2014. Telomerase activation: a potential key modulator for human healthspan and longevity. Ageing Res. Rev. 15C, 1–5. Bodovitz, S., Klein, W.L., 1996. Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 271, 4436–4440. Bogdanovic, N., Bretillon, L., Lund, E.G., Diczfalusy, U., Lannfelt, L., Winblad, B., Russell, D.W., Björkhem, I., 2001. On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci. Lett. 314, 45–48. Boitard, C., 2002. Insulin secretion in type 2 diabetes: clinical aspects. Diabetes Metab. 28, 4S33-4S38. Boumhras, M., 2012. Evaluation de la toxicité de moules de la Côte Atlantique Marocaine utilisées comme bioindicateurs de contamination: étude in vivo et in vitro sur des rongeurs et des cellules béta-pancréatiques murines (MIN-6). University of Bourgogne, University of Settat, Dijon, France/Marocco (Ph.D. Thesis). Bretillon, L., Sidén, A., Wahlund, L.O., Lütjohann, D., Minthon, L., Crisby, M., Hillert, J., Groth, C.G., Diczfalusy, U., Björkhem, I., 2000. Plasma levels of 24Shydroxycholesterol in patients with neurological diseases. Neurosci. Lett. 293, 87–90. Bretillon, L., Diczfalusy, U., Björkhem, I., Maire, M.A., Martine, L., Joffre, C., Acar, N., Bron, A., Creuzot-Garcher, C., 2007. Cholesterol-24S-hydroxylase (CYP46A1) is specifically expressed in neurons of the neural retina. Curr. Eye Res. 32, 361–366. Brian, G., Taylor, H., 2001. Cataract blindness-challenges for the 21st century. Bull. World Health Organ. 79, 249–256. Brown, A.J., Jessup, W., 1999. Oxysterols and atherosclerosis. Atherosclerosis 142, 1–28. Brown 3rd, J., Theisler, C., Silberman, S., Magnuson, D., Gottardi-Littell, N., Lee, J.M., Yager, D., Crowley, J., Sambamurti, K., Rahman, M.M., Reiss, A.B., Eckman, C.B., Wolozin, B., 2004. Differential expression of cholesterol hydroxylases in Alzheimer’s disease. J. Biol. Chem. 279, 34674–34681. Bu, G., 2009. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333–344. Burns, M., Duff., K., 2002. Cholesterol in Alzheimer’s disease and tauopathy. Ann. N.Y. Acad. Sci. 977, 367–375. Buttari, B., Segoni, L., Profumo, E., D’Arcangelo, D., Rossi, S., Facchiano, F., Businaro, R., Iuliano, L., Riganò, R., 2013. 7-Oxo-cholesterol potentiates pro-inflammatory signaling in human M1 and M2 macrophages. Biochem. Pharmacol. 86, 130–137. Catarino, S., Bento, C.F., Brito, A., Murteira, E., Fernandes, A.F., Pereira, P., 2012. Regulation of the expression of interleukin-8 induced by 25-hydroxycholesterol in retinal pigment epithelium cells. Acta Ophtalmol. 90, 255–263. Cenedella, R.J., 1996. Cholesterol and cataracts. Surv. Ophthalmol. 40, 320–337. Cheng, Y.W., Kang, J.J., Shih, Y.L., Lo, Y.L., Wang, C.F., 2005. Cholesterol-3-beta, 5-alpha, 6-beta-triol induced genotoxicity through reactive oxygen species formation. Food Chem. Toxicol. 43, 617–622. Curcio, C.A., Presley, J.B., Malek, G., Medeiros, N.E., Avery, D.V., Kruth, H.S., 2005. Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp. Eye Res. 81, 731–741. Dasari, B., Prasanthi, J.R., Marwarha, G., Singh, B.B., Ghribi, O., 2010. The oxysterol 27-hydroxycholesterol increases beta-amyloid and oxidative stress in retinal pigment epithelial cells. BMC Ophthalmol. 10, 22. Dasari, B., Prasanthi, J.R., Marwarha, G., Singh, B.B., Ghribi, O., 2011. Cholesterolenriched diet causes age-related macular degeneration-like pathology in rabbit retina. BMC Ophthalmol. 11, 22.

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Daugvilaite, V., Arfelt, K.N., Benned-Jensen, T., Sailer, A.W., Rosenkilde, M.M., 2014. EBI2-targeting oxysterols: a moving story. Eur. J. Immunol., http://dx.doi.org/10.1002/eji.201444493. De Boussac, H., Alioui, A., Viennois, E., Dufour, J., Trousson, A., Vega, A., Guy, L., Volle, D.H., Lobaccaro, J.M., Baron, S., 2013a. Oxysterol receptors and their therapeutic applications in cancer conditions. Expert Opin. Ther. Targets 17, 1029–1038. De Boussac, H., Pommier, A.J., Dufour, J., Trousson, A., Caira, F., Volle, D.H., Baron, S., Lobaccaro, J.M., 2013b. LXR, prostate cancer and cholesterol: the good, the bad and the ugly. Am. J. Cancer Res. 3, 58–69. Deckert, V., Perségol, L., Viens, L., Lizard, G., Athias, A., Lallemant, C., Gambert, P., Lagrost, L., 1997. Inhibitors of arterial relaxation among components of human oxidized low-density lipoproteins Cholesterol derivatives oxidized in position 7 are potent inhibitors of endothelium-dependent relaxation. Circulation 95, 723–731. Deckert, V., Duverneuil, L., Poupon, S., Monier, S., Le Guern, N., Lizard, G., Masson, D., Lagrost, L., 2002. The impairment of endothelium-dependent arterial relaxation by 7-ketocholesterol is associated with an early activation of protein kinase C. Br. J. Pharmacol. 137, 655–662. De Medina, P., Paillasse, M.R., Ségala, G., Khallouki, F., Brillouet, S., Dalenc, F., Courbon, F., Record, M., Poirot, M., Silvente-Poirot, S., 2011. Importance of cholesterol and oxysterols metabolism in the pharmacology of tamoxifen and other AEBS ligands. Chem. Phys. Lipids 164, 432–437. De Medina, P., Paillasse, M.R., Segala, G., Voisin, M., Mhamdi, L., Dalenc, F., Lacroix-Triki, M., Filleron, T., Pont, F., Saati, T.A., Morisseau, C., Hammock, B.D., Silvente-Poirot, S., Poirot, M., 2013. Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. Nat. Commun. 24, 1840. Dentchev, T., Milam, A.H., Lee, V.M., Trojanowski, J.Q., Dunaief, J.L., 2003. Amyloidbeta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. Mol. Vision 9, 184–190. Di Frisco, S., De Ruggieri, P., Ercolli, A., 1953. Isolation of cerebrosterol from human brain. Boll. Soc. Ital Biol. Sper. 29, 1351–1352. Di Paolo, G., Kim, T.W., 2011. Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat. Rev. Neurosci. 12, 284–296. Diczfalusy, U., 2013. On the formation and possible biological role of 25hydroxycholesterol. Biochimie 95, 455–460. Ding, X., Patel, M., Chan, C.C., 2009. Molecular pathology of age-related macular degeneration. Prog. Retin. Eye. Res. 28, 1–18. Dreyfus, M.A., Tolocka, M.P., Dodds, S.M., Dykins, J., Johnston, M.V., 2005. Cholesterol ozonolysis: kinetics, mechanism, and oligomer products. J. Phys. Chem. A 109, 6242–6248. Dufour, J., Viennois, E., De Boussac, H., Baron, S., Lobaccaro, J.M., 2012. Oxysterol receptors AKT and prostate cancer. Curr. Opin. Pharmacol. 12, 724–728. Dugas, B., Charbonnier, S., Baarine, M., Ragot, K., Delmas, D., Ménétrier, F., Lherminier, J., Malvitte, L., Khalfaoui, T., Bron, A., Creuzot-Garcher, C., Latruffe, N., Lizard, G., 2010. Effects of oxysterols on cell viability, inflammatory cytokines, VEGF, and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol. Eur. J. Nutr. 49, 435–446. Duran, M.J., Pierre, S.V., Lesnik, P., Pieroni, G., Bourdeaux, M., Dignat-Georges, F., Sampol, J., Maixent, J.M., 2010. ketocholesterol inhibits Na K-ATPase activity by decreasing expression of its ␣1-subunit and membrane fluidity in human endothelial cells. Cell. Mol. Biol. 56, 1434–1441. DuSell, C.D., Nelson, E.R., Wang, X., Abdo, J., Mödder, U.I., Umetani, M., Gesty-Palmer, D., Javitt, N.B., Khosla, S., McDonnell, D.P., 2010. The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis. Endocrinology 151, 3675–3685. Ehrlich, D., Humpel, C., 2012. Chronic vascular risk factors (cholesterol, homocysteine, ethanol) impair spatial memory, decline cholinergic neurons and induce blood-brain barrier leakage in rats in vivo. J. Neurol. Sci. 322, 92–95. Ehehalt, R., Keller, P., Haass, C., Thiele, C., Simons, K., 2003. Amyloidogenic processing of the Alzheimer ␤-amyloid precursor protein depends on lipid rafts. J. Cell Biol. 160, 113–123. Famer, D., Meaney, S., Mousavi, M., Nordberg, A., Bjorkhem, I., Crisby, M., 2007. Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway. Biochem. Biophys. Res. Commun. 359, 46–50. Fassbender, K., Simons, M., Bergmann, C., Stroick, M., Lutjohann, D., Keller, P., Runz, H., Kuhl, S., Bertsch, T., von Bergmann, K., Hennerici, M., Beyreuther, K., Hartmann, T., 2001. Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A. 98, 5856–5861. Feldman, G.L., Feldman, L.S., 1965. New concepts of human lenticular lipids and their possible role in cataract. Invest. Ophtalmol. 4, 162–166. Fiolaki, A., Tsamis, K.I., Milionis, H.J., Kyritsis, A.P., Kosmidou, M., Giannopoulos, S., 2014. Atherosclerosis, biomarkers of atherosclerosis and Alzheimer’s disease. Int. J. Neurosci. 124, 1–11. Fiorenza, M.T., Dardis, A., Canterini, S., Erickson, R.P., 2013. Cholesterol metabolismassociated molecules in late onset Alzheimer’s disease. J. Biol. Regul. Homeost. Agents 27, 23–35. Fotenos, A., Snyder, A., 2005. Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD. Neurology 64, 1032–1039. Fourgeux, C., Martine, L., Acar, N., Bron, A.M., Creuzot-Garcher, C.P., Bretillon, L., 2014. In vivo consequences of cholesterol-24S-hydroxylase (CYP46A1) inhibition by voriconazole on cholesterol homeostasis and function in the rat retina. Biochem. Biophys. Res. Commun. 446, 775–781.


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G Model ARR 537 1–15 12 1100 1101 1102 1103 1104 1105 1106 1107 1108 1109 1110 Q9 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185


Freeman, M.R., Solomon, K.R., 2004. Cholesterol and prostate cancer. J. Cell Biochem. 91, 54–69. Galea, E., Launay, N., Portero-Otin, M., Ruiz, M., Pamplona, R., Aubourg, P., Ferrer, I., Pujol, A., 2012. Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: a paradigm for multifactorial neurodegenerative diseases? Biochim. Biophys. Acta 1822, 1475–1488. Gamba, P., Guglielmotto, M., Testa, G., Monteleone, D., Zerbinati, C., Gargiulo, S., Biasi, F., Iuliano, L., Giaccone, G., Mauro, A., Poli, G., Tamagno, E., Leonarduzzi, G., 2014. Up-regulation of ␤-amyloidogenesis in neuron-like human cells by both 24and 27-hydroxycholesterol: protective effect of N-acetyl-cysteine. Aging Cell, 1–12 Gao, C., Hölscher, C., Liu, Y., Li, L., 2011. GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease. Rev. Neurosci. 23, 1–11. Garcia, A., Muniz, M., Souzae Silva, H., Da Silva, H., Athayde-Junior, L., 2009. Cyp46 polymorphisms in Alzheimer’s disease: a review. J. Mol. Neurosci. 39, 342–345. Gargiulo, S., Sottero, B., Gamba, P., Chiarpotto, E., Poli, G., Leonarduzzi, G., 2011. Plaque oxysterols induce unbalanced up-regulation of matrix metalloproteinase-9 in macrophagic cells through redox-sensitive signaling pathways: implications regarding the vulnerability of atherosclerotic lesions. Free Radic. Biol. Med. 51, 844–855. Gargiulo, S., Gamba, P., Poli, G., Leonarduzzi, G., 2014. Metalloproteinases and metalloproteinase inhibitors in age-related diseases. Curr. Pharm. Des. 20, 2993–3018. Gatto, D., Brink, R., 2013. B cell localization: regulation by EBI2 and its oxysterol ligand. Trends Immunol. 34, 336–341. Geyeregger, R., Zeyda, M., Stulnig, T.M., 2006. Liver X receptors in cardiovascular and metabolic disease. Cell Mol. Life Sci. 63, 524–539. Ghribi, O., Larsen, B., Schrag, M., Herman, M.M., 2006. High cholesterol content in neurons increases BACE, beta-amyloid, and phosphorylated tau levels in rabbit hippocampus. Exp. Neurol. 200, 460–467. Girão, H., Mota, M.C., Ramalho, J., Pereira, P., 1998. Cholesterol oxides accumulate in human cataracts. Exp. Eye Res. 66, 645–652. Gramajo, A.L., Zacharias, L.C., Neekhra, A., Luthra, S., Atilano, S.R., Chwa, M., Brown, D.J., Kuppermann, B.D., Kenney, M.C., 2010. Mitochondrial DNA damage induced by 7-ketocholesterol in human retinal pigment epithelial cells in vitro. Invest. Ophthalmol. Visual Sci. 51, 1164–1170. Hannedouche, S., Zhang, J., Yi, T., Shen, W., Nguyen, D., Pereira, J.P., Guerini, D., Baumgarten, B.U., Roggo, S., Wen, B., Knochenmuss, R., Noël, S., Gessier, F., Kelly, L.M., Vanek, M., Laurent, S., Preuss, I., Miault, C., Christen, I., Karuna, R., Li, W., Koo, D.I., Suply, T., Schmedt, C., Peters, E.C., Falchetto, R., Katopodis, A., Spanka, C., Roy, M.O., Detheux, M., Chen, Y.A., Schultz, P.G., Cho, C.Y., Seuwen, K., Cyster, J.G., Sailer, A.W., 2011. Oxysterols direct immune cell migration via EBI2. Nature 475, 524–527. Harman, D., 2003. The free radical theory of aging. Antioxid. Redox Signal. 5, 557–561. Hayden, J.M., Brachova, L., Higgins, K., Obermiller, L., Sevanian, A., Khandrika, S., Reaven, P.D., 2002. Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol. J. Lipid Res. 43, 26–35. He, C., Zhu, H., Zhang, W., Okon, I., Wang, Q., Li, H., Le, Y.Z., Xie, Z., 2013. 7 Ketocholesterol induces autophagy in vascular smooth muscle cells through Nox4 and Atg4B. Am. J. Pathol. 183, 626–637. Helmschrodt, C., Becker, S., Schröter, J., Hecht, M., Aust, G., Thiery, J., Ceglarek, U., 2013. Fast LC-MS/MS analysis of free oxysterols derived from reactive oxygen species in human plasma and carotid plaque. Clin. Chim. Acta 425, 3–8. Heverin, M., Bogdanovic, N., Lutjohann, D., Bayer, T., Pikuleva, I., Bretillon, L., Diczfalusy, U., Winblad, B., Bjorkhem, I., 2004. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer’s disease. J. Lipid Res. 45, 186–193. Hoang, J.J., Baron, S., Volle, D.H., Lobaccaro, J.M., Trousson, A., 2013. Lipids, LXRs and prostate cancer: are HDACs a new link? Biochem. Pharmacol. 86, 168–174. Hu, H., Hilton, M.J., Tu, X., Yu, K., Ornitz, D.M., Long, F., 2005. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132, 49–60. Huang, J.D., Amaral, J., Lee, J.W., Larrayoz, I.M., Rodriguez, I.R., 2012. Sterculic acid antagonizes 7-ketocholesterol-mediated inflammation and inhibits choroidal neovascularization. Biochim. Biophys. Acta 1821, 637–646. Hudry, E., Van Dam, D., Kulik, W., De Deyn, P.P., Stet, F.S., Ahouansou, O., Benraiss, A., Delacourte, A., Bougnères, P., Aubourg, P., Cartier, N., 2010. Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer’s disease. Mol. Ther. 18, 44–53. Iuliano, L., 2011. Pathways of cholesterol oxidation via non-enzymatic mechanisms. Chem. Phys. Lipids 164, 457–468. Jack Jr., C.R., Lowe, V.J., Weigand, S.D., Wiste, H.J., Senjem, M.L., Knopman, D.S., Shiung, M.M., Gunter, J.L., Boeve, B.F., Kemp, B.J., Weiner, M., Petersen, R.C., 2009. Alzheimer’s Disease Neuroimaging Initiative, Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease, implications for sequence of pathological events in Alzheimer’s disease. Brain 132, 1355–1365. Jack Jr., C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., Petersen, R.C., Trojanowski, J.Q., 2010. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128. Javitt, N.B., 2002. Cholesterol, hydroxycholesterols, and bile acids. Biochem. Res. Commun. 292, 1147–1153. Javitt, N.B., Javitt, J.C., 2009. The retinal oxysterol pathway: a unifying hypothesis for the cause of age-related macular degeneration. Curr. Opin. Ophthalmol. 20, 151–157.

Jenny, N.S., 2012. Inflammation in aging: cause, effect, or both? Discovery Med. 13, 451–460. Jia, G., Cheng, G., Agrawal, D.K., 2007. Autophagy of vascular smooth muscle cells in atherosclerotic lesions. Autophagy 3, 63–64. Joffre, C., Leclère, L., Buteau, B., Martine, L., Cabaret, S., Malvitte, L., Acar, N., Lizard, G., Bron, A., Creuzot-Garcher, C., Bretillon, L., 2007. Oxysterols induced inflammation and oxidation in primary porcine retinal pigment epithelial cells. Curr. Eye Res. 32, 271–280. Johnson, M.L., Harnish, K., Nusse, R., Van Hul, W., 2004. LRP5 and Wnt signaling: a union made for bone. J. Bone Miner. Res. 19, 1749–1757. Joseph, S.B., Castrillo, A., Laffitte, B.A., Mangelsdorf, D.J., Tontonoz, P., 2003. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med. 9, 213–219. Jusakul, A., Yongvanit, P., Loilome, W., Namwat, N., Kuver, R., 2011. Mechanisms of oxysterol-induced carcinogenesis. Lipids Health Dis. 10, 44. Kahn, E., Ménétrier, F., Vejux, A., Montange, T., Dumas, D., Riedinger, J.M., Frouin, F., Tourneur, Y., Brau, F., Stoltz, J.F., Lizard, G., 2006. Flow cytometry and spectral imaging multiphoton microscopy analysis of CD36 expression with quantum dots 605 of untreated and 7-ketocholesterol-treated human monocytic cells. Anal. Quant. Cytol. Histol. 28, 316–330. Kha, H.T., Basseri, B., Shouhed, D., Richardson, J., Tetradis, S., Hahn, T.J., Parhami, F., 2004. Oxysterols regulate differentiation of mesenchymal stem cells: pro-bone and anti-fat. J. Bone Miner. Res. 19, 830–840. Khalifa, S.A., de Medina, P., Erlandsson, A., El-Seedi, H.R., Silvente-Poirot, S., Poirot, M., 2014. The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells. Biochem. Biophys. Res. Commun. 446, 681–686. Khatib, S., Vaya, J., 2014. Oxysterols and symptomatic versus asymptomatic human atherosclerotic plaque. Biochem. Biophys. Res. Commun. 446, 709–713. Kim, W.K., Meliton, V., Amantea, C.M., Hahn, T.J., Parhami, F., 2007. 20(S)hydroxycholesterol inhibits PPARgamma expression and adipogenic differentiation of bone marrow stromal cells through a hedgehog-dependent mechanism. J. Bone Miner. Res. 22, 1711–1719. Kim, D.H., Frangos, J.A., 2008. Effects of amyloid ␤-peptides on the lysis tension of lipid bilayer vesicles containing oxysterols. Biophys. J. 95, 620–628. Kim, W.S., Chan, S.L., Hill, A.F., Guillemin, G.J., Garner, B., 2009. Impact of 27hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons. J. Alzheimers Dis. 16, 121–131. Kolsch, H., Heun, R., Kerksiek, A., Bergmann, K.V., Maier, W., Lutjohann, D., 2004. Altered levels of plasma 24S- and 27-hydroxycholesterol in demented patients. Neurosci. Lett. 368, 303–308. Koschack, J., Lütjohann, D., Schmidt-Samoa, C., Irle, E., 2009. Serum 24Shydroxycholesterol and hippocampal size in middle-aged normal individuals. Neurobiol. Aging 30, 898–902. Kriˇstofiková, Z., Kˇríˇz, Z., Rípová, D., Koˇca, J., 2012. Interactions of amyloid â peptide Z. Kristofiková, 1–40 and cerebrosterol. Neurochem. Res. 37, 604–613. Larrayoz, I.M., Huang, J.D., Lee, J.W., Pascual, I., Rodriguez, I.R., 2010. 7Ketocholesterol-induced inflammation: involvement of multiple kinase signaling pathways via NF kappa B but independently of reactive oxygen species formation. Invest. Ophthalmol. Visual Sci. 51, 4942–4955. Larsson, H., Böttiger, Y., Iuliano, L., Diczfalusy, U., 2007. In vivo interconversion of 7beta-hydroxycholesterol and 7-ketocholesterol, potential surrogate markers for oxidative stress. Free Radical Biol. Med. 43, 695–701. Leduc, V., Jasmin-Bélanger, S., Poirier, J., 2010. APOE and cholesterol homeostasis in Alzheimer’s disease. Trends Mol. Med. 16, 469–477. Lee, C.S., Park, W.J., Han, E.S., Bang, H., 2007. Differential modulation of 7ketocholesterol toxicity against PC12 cells by calmodulin antagonists and Ca2+ channel blockers. Neurochem. Res. 32, 87–98. Lemaire, S., Lizard, G., Monier, S., Miguet, C., Gueldry, S., Volot, F., Gambert, P., Néel, D., 1998. Different patterns of IL-1beta secretion, adhesion molecule expression and apoptosis induction in human endothelial cells treated with 7alpha-, 7betahydroxycholesterol, or 7-ketocholesterol. FEBS Lett. 440, 434–439. Lemaire-Ewing, S., Prunet, C., Montange, T., Vejux, A., Berthier, A., Bessède, G., Corcos, L., Gambert, P., Néel, D., Lizard, G., 2005. Comparison of the cytotoxic, prooxidant and pro-inflammatory characteristics of different oxysterols. Cell Biol. Toxicol. 21, 97–114. Lemaire-Ewing, S., Berthier, A., Royer, M.C., Logette, E., Corcos, L., Bouchot, A., Monier, S., Prunet, C., Raveneau, M., Rébé, C., Desrumaux, C., Lizard, G., Néel, D., 2009. 7beta-Hydroxycholesterol and 25-hydroxycholesterol-induced interleukin-8 secretion involves a calcium-dependent activation of c-fos via the ERK1/2 signaling pathway in THP-1 cells: oxysterols-induced IL-8 secretion is calciumdependent. Cell Biol. Toxicol. 25, 127–139. Leonarduzzi, G., Vizio, B., Sottero, B., Verde, V., Gamba, P., Mascia, C., Chiarpotto, E., Poli, G., Biasi, F., 2006. Early involvement of ROS overproduction in apoptosis induced by 7-ketocholesterol. Antioxid. Redox Signal. 8, 375–380. Leonarduzzi, G., Gargiulo, S., Gamba, P., Perrelli, M.G., Castellano, I., Sapino, A., Sottero, B., Poli, G., 2010. Molecular signaling operated by a diet-compatible mixture of oxysterols in up-regulating CD36 receptor in CD68 positive cells. Mol. Nutr. Food. Res. 54, S31–S41. Leoni, V., Caccia, C., 2011. Oxysterols as biomarkers in neurodegenerative diseases. Chem. Phys. Lipids 164, 515–524. Li, W., Ghosh, M., Eftekhari, S., Yuan, X.M., 2011. Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols. Biochem. Biophys. Res. Commun. 409, 711–716.


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Lichtstein, D., McGowan, M.H., Russell, P., Carper, D.A., 2000. Digitalis and digitalis like compounds down-regulate gene expression of the intracellular signaling protein 14-3-3 in rat lens. Hypertens. Res. 23, S51–S53. Liochev, S.I., 2013. Reactive oxygen species and the free radical theory of aging. Free Radical Biol. Med. 60, 1–4. Liu, H., Yuan, L., Xu, S., Zhang, T., Wang, K., 2004. Cholestane-3beta, 5alpha, 6betatriol promotes vascular smooth muscle cells calcification. Life Sci. 76, 533–543. Liu, Y., Sharpless, N.E., 2009. Suppressor mechanisms in immune aging. Curr. Opin. Immunol. 21, 431–439. Liu, H., Yuan, L., Xu, S., Wang, K., Zhang, T., 2005. Cholestane-3beta, 5alpha, 6betatriol inhibits osteoblastic differentiation and promotes apoptosis of rat bone marrow stromal cells. J. Cell Biochem. 96, 198–208. Lizard, G., Deckert, V., Dubrez, L., Moisant, M., Gambert, P., Lagrost, L., 1996. Induction of apoptosis in endothelial cells treated with cholesterol oxides. Am. J. Pathol. 148, 1625–1638. López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2013. The hallmarks of aging. Cell 153, 1194–1217. Lordan, S., Mackrill, J.J., O’Brien, N.M., 2009. Oxysterols and mechanisms of apoptotic signaling: implications in the pathology of degenerative diseases. J. Nutr. Biochem. 20, 321–336. Lubos, E., Handy, D.E., Loscalzo, J., 2008. Role of oxidative stress and nitric oxide in atherothrombosis. Front Biosci. 13, 5323–5344. Lund, E., Kerr, T.A., Sakai, J., Li, W.P., Russell, D.W., 1998. cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytoptic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism. J. Biol. Chem. 273, 34316–34327. Lund, E.G., Guileyardo, J.M., Russell, D.W., 1999. cDNA cloning of cholesterol 24hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc. Natl. Acad. Sci. U.S.A. 96, 7238–7243. Luthra, S., Fardin, B., Dong, J., Hertzog, D., Kamjoo, S., Gebremariam, S., Butani, V., Narayanan, R., Mungcal, J.K., Kuppermann, B.D., Kenney, M.C., 2006. Activation of caspase-8 and caspase-12 pathways by 7-ketocholesterol in human retinal pigment epithelial cells. Invest. Ophthalmol. Visual Sci. 47, 5569–5675. Lütjohann, D., Papassotiropoulos, A., Björkhem, I., Locatelli, S., Bagli, M., Oehring, R.D., Schlegel, U., Jessen, F., Rao, M.L., von Bergmann, K., Heun, R., 2000. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J. Lipid Res. 41, 195–198. Luu, B., 1995. From cholesterol to oxysterols current data. C.R. Seances Soc. Biol. Fil. 189, 827–837. Malvitte, L., Montange, T., Vejux, A., Joffre, C., Bron, A., Creuzot-Garcher, C., Lizard, G., 2008. Activation of a caspase-3-independent mode of cell death associated with lysosomal destabilization in cultured human retinal pigment epithelial cells (ARPE-19) exposed to 7beta-hydroxycholesterol. Curr. Eye Res. 33, 769–781. Marchant, N.L., Reed, B.R., Sanossian, N., Madison, C.M., Kriger, S., Dhada, R., Mack, W.J., DeCarli, C., Weiner, M.W., Mungas, D.M., Chui, H.C., Jagust, W.J., 2013. The aging brain and cognition: contribution of vascular injury and a␤ to mild cognitive dysfunction. JAMA Neurol. 70, 488–495. Martin, M.G., Ahmed, T., Korovaichuk, A., Venero, C., Menchón, S.A., Salas, I., Munck, S., Herreras, O., Balschun, D., Dotti, C.G., 2014. Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents. EMBO Mol. Med. 6, 902–917. Martin, M., Dotti, C.G., Ledesma, M.D., 2010. Brain cholesterol in normal and pathological aging. Biochim. Biophys. Acta 1801, 934–944. Martin, M.G., Perga, S., Trovò, L., Rasola, A., Holm, P., Rantamäki, T., Harkany, T., Castrén, E., Chiara, F., Dotti, C.G., 2008. Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro. Mol. Biol. Cell. 19, 2101–2112. Mast, N., White, M.A., Bjorkhem, I., Johnson, E.F., Stout, C.D., Pikuleva, I.A., 2008. Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl. Acad. Sci. U.S.A. 105, 9546–9551. Matsui, H., Okumura, K., Mukawa, H., Hibino, M., Toki, Y., Ito, T., 1997. Increased oxysterol contents in diabetic rat hearts: their involvement in diabetic cardiomyopathy. Can. J. Cardiol. 13, 373–379. Maulik, M., Westaway, D., Jhamandas, J.H., Kar, S., 2013. Role of cholesterol in APP metabolism and its significance in Alzheimer’s disease pathogenesis. Mol. Neurobiol. 47, 37–63. McGowan, M.H., Russell, P., Carper, D.A., Lichtstein, D., 1999. Na+ , K+ -ATPase inhibitors down-regulate gene expression of the intracellular signaling protein 14-3-3 in rat lens. J. Pharmacol. Exp. Ther. 289, 1559–1563. ˜ M., Varo, N., Mugueta, C., Restituto, P., Ansorena, D., Astiasarán, Menéndez-Carreno, I., 2011. Correlation between serum content of the main COPs (cholesterol oxidation products) from autoxidation and cardiovascular risk factors. Nutr. Hosp. 26, 144–151. Miguet, C., Monier, S., Bettaieb, A., Athias, A., Besséde, G., Laubriet, A., Lemaire, S., Néel, D., Gambert, P., Lizard, G., 2001. Ceramide generation occurring during 7beta-hydroxycholesterol- and 7-ketocholesterol-induced apoptosis is caspase independent and is not required to trigger cell death. Cell Death Differ. 8, 83–99. Min, S.W., Sohn, P.D., Cho, S.H., Swanson, R.A., Gan, L., 2013. Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front. Aging Neurosci. 25 (5), 53. Mintzer, E., Charles, G., Gordon, S., 2010. Interaction of two oxysterols, 7ketocholesterol and 25-hydroxycholesterol, with phosphatidylcholine and sphingomyelin in model membranes. Chem. Phys. Lipids 163, 586–593. Monier, S., Samadi, M., Prunet, C., Denance, M., Laubriet, A., Athias, A., Berthier, A., Steinmetz, E., Jürgens, G., Nègre-Salvayre, A., Bessède, G., Lemaire-Ewing, S., Néel, D., Gambert, P., Lizard, G., 2003. Impairment of the cytotoxic and oxidative

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activities of 7beta-hydroxycholesterol and 7-ketocholesterol by esterification with oleate. Biochem. Biophys. Res. Commun. 303, 814–824. Monte, M.J., Marin, J.J., Antelo, A., Vazquez-Tato, J., 2009. Bile acids: chemistry, physiology, and pathophysiology. World J. Gastroenterol. 15, 804–816. Neekhra, A., Luthra, S., Chwa, M., Seigel, G., Gramajo, A.L., Kuppermann, B.D., Kenney, M.C., 2007. Caspase-8 -12, and -3 activation by 7-ketocholesterol in retinal neurosensory cells. Invest. Ophthalmol. Visual Sci. 48, 1362–1367. Negre-Salvayre, A., Auge, N., Ayala, V., Basaga, H., Boada, J., Brenke, R., Chapple, S., Cohen, G., Feher, J., Grune, T., Lengyel, G., Mann, G.E., Pamplona, R., Poli, G., Portero-Otin, M., Riahi, Y., Salvayre, R., Sasson, S., Serrano, J., Shamni, O., Siems, W., Siow, R.C., Wiswedel, I., Zarkovic, K., Zarkovic, N., 2010. Pathological aspects of lipid peroxidation. Free Radical Res. 44, 1125–1171. Nelson, E.R., Wardell, S.E., McDonnell, D.P., 2013. The molecular mechanisms underlying the pharmacological actions of estrogens SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone 53, 42–50. Nury, T., Samadi, M., Zarrouk, A., Riedinger, J.M., Lizard, G., 2013. Improved synthesis and in vitro evaluation of the cytotoxic profile of oxysterols oxidized at C4 (4␣- and 4␤-hydroxycholesterol) and C7 (7-ketocholesterol, 7␣- and 7␤hydroxycholesterol) on cells of the central nervous system. Eur. J. Med. Chem. 70, 558–567. Nury, T., Zarrouk, A., Vejux, A., Doria, M., Riedinger, J.M., Delage-Mourroux, R., Lizard, G., 2014. Induction of oxiapoptophagy, a mixed mode of cell death associated with oxidative stress, apoptosis and autophagy, on 7-ketocholesterol-treated 158N murine oligodendrocytes: impairment by ␣-tocopherol. Biochem. Biophys. Res. Commun. 446, 714–719. Odermatt, A., Klusonova, P., 2014. 11␤-Hydroxysteroid dehydrogenase 1: regeneration of active glucocorticoids is only part of the story. J. Steroid Biochem. Mol. Biol., http://dx.doi.org/10.1016/j.jsbmb.2014.08.011 (pii: S09600760(14)00190-3). Okabe, A., Urano, Y., Itoh, S., Suda, N., Kotani, R., Nishimura, Y., Saito, Y., Noguchi, N., 2013. Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death. Redox Biol. 2, 28–35. Olkkonen, V.M., Li, S., 2013. Oxysterol-binding proteins: sterol and phosphoinositide sensors coordinating transport, signaling and metabolism. Prog. Lipid Res. 52, 529–538. Otaegui-Arrazola, A., Menendez-Carreno, M., Ansorena, D., Astiasaran, I., 2010. Oxysterols: a world to explore. Food Chem. Toxicol. 48, 3289–3303. Papassotiropoulos, A., Lütjohann, D., Bagli, M., Locatelli, S., Jessen, F., Rao, M.L., Maier, W., Björkhem, I., von Bergmann, K., Heun, R., 2000. Plasma 24S-hydroxycholesterol, a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer’s disease. Neuroreport 11, 1959–1962. Papassotiropoulos, A., Streffer, J., Tsolaki, M., Schmid, S., Thal, D., Nicosia, F., Iakovidou, V., Maddalena, A., Lutjohann, D., Ghe-bremedhin, E., Hegi, T., Pasch, T., Traxler, M., Bruhl, A., Benussi, L., Binetti, G., Braak, H., Nitsch, R., Hock, C., 2003. Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch. Neurol. 60, 29–35. Pedruzzi, E., Guichard, C., Ollivier, V., Driss, F., Fay, M., Prunet, C., Marie, J.C., Pouzet, C., Samadi, M., Elbim, C., O’dowd, Y., Bens, M., Vandewalle, A., Gougerot-Pocidalo, M.A., Lizard, G., Ogier-Denis, E., 2004. NAD(P)H oxidase Nox-4 mediates 7ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. Mol. Cell. Biol. 24, 10703–10717. Petit-Paitel, A., 2010. GSK-3beta: a central kinase for neurodegenerative diseases? Med. Sci. (Paris) 26, 516–521. Phan, H.T., Hata, T., Morita, M., Yoda, T., Hamada, T., Vestergaard, M.C., Takagi, M., 2013. The effect of oxysterols on the interaction of Alzheimer’s amyloid beta with model membranes. Biochim. Biophys. Acta 1828, 2487–2495. Pikuleva, I.A., 2006. Cholesterol-metabolizing cytochromes P450. Drug Metab. Dispos. 34, 513–520. Pikuleva, I.A., Curcio, C.A., 2014. Cholesterol in the retina: the best is yet to come. Prog. Retin. Eye Res 41C, 64–89. Poli, G., Biasi, F., Leonarduzzi, G., 2013. Oxysterols in the pathogenesis of major chronic diseases. Redox Biol. 1, 125–130. Pommier, A.J., Alves, G., Viennois, E., Bernard, S., Communal, Y., Sion, B., Marceau, G., Damon, C., Mouzat, K., Caira, F., Baron, S., Lobaccaro, J.M., 2010. Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. Oncogene 29, 2712–2723. Prasanthi, J.R., Huls, A., Thomasson, S., Thompson, A., Schommer, E., Ghribi, O., 2009. Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells. Mol. Neurodegener. 4, 1. Prunet, C., Montange, T., Véjux, A., Laubriet, A., Rohmer, J.F., Riedinger, J.M., Athias, A., Lemaire-Ewing, S., Néel, D., Petit, J.M., Steinmetz, E., Brenot, R., Gambert, P., Lizard, G., 2006a. Multiplexed flow cytometric analyses of pro- and anti-inflammatory cytokines in the culture media of oxysterol-treated human monocytic cells and in the sera of atherosclerotic patients. Cytometry A 69, 359–373. Prunet, C., Petit, J.M., Ecarnot-Laubriet, A., Athias, A., Miguet-Alfonsi, C., Rohmer, J.F., Steinmetz, E., Néel, D., Gambert, P., Lizard, G., 2006b. High circulating levels of 7beta- and 7alpha-hydroxycholesterol and presence of apoptotic and oxidative markers in arterial lesions of normocholesterolemic atherosclerotic patients undergoing endarterectomy. Pathol. Biol. (Paris) 54, 22–32. Pulfer, M.K., Taube, C., Gelfand, E., Murphy, R.C., 2005. Ozone exposure in vivo and formation of biologically active oxysterols in the lung. J. Pharmacol. Exp. Ther. 312, 256–264.


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Ragot, K., Delmas, D., Athias, A., Nury, T., Baarine, M., Lizard, G., 2011. ␣-Tocopherol impairs 7-ketocholesterol-induced caspase-3-dependent apoptosis involving GSK-3 activation and Mcl-1 degradation on 158N murine oligodendrocytes. Chem. Phys. Lipids 164, 469–478. Ragot, K., Mackrill, J.J., Zarrouk, A., Nury, T., Aires, V., Jacquin, A., Athias, A., Pais de Barros, J.P., Véjux, A., Riedinger, J.M., Delmas, D., Lizard, G., 2013. Absence of correlation between oxysterol accumulation in lipid raft microdomains, calcium increase, and apoptosis induction on 158N murine oligodendrocytes. Biochem. Pharmacol. 86, 67–79. Reddy, B.S., Martin, C.W., Wynder, E.L., 1997. Fecal bile acids and cholesterol metabolites of patients with ulcerative colitis, a high-risk group for development of colon cancer. Cancer Res. 37, 1697–1701. Reddy, B.S., Watanabe, K., 1979. Effect of cholesterol metabolites and promoting effect of lithocholic acid in colon carcinogenesis in germ-free and conventional F344 rats. Cancer Res. 39, 1521–1524. Reed, B., Villeneuve, S., Mack, W., DeCarli, C., Chui, H.C., Jagust, W., 2014. Associations between serum cholesterol levels and cerebral amyloidosis. JAMA Neurol. 71, 195–200. Richardson, J.A., Amantea, C.M., Kianmahd, B., Tetradis, S., Lieberman, J.R., Hahn, T.J., Parhami, F., 2007. Oxysterol-induced osteoblastic differentiation of pluripotent mesenchymal cells is mediated through a PKC- and PKA-dependent pathway. J. Biol. Chem. 100, 1131–1145. Riggs, B.L., Melton, L.J., 1992. The prevention and treatment of osteoporosis. New Engl. J. Med. 327, 620–627. Robbins, D.J., Fei, D.L., Riobo, N.A., 2012. The Hedgehog signal transduction network. Sci. Signal. 5 (246), re6. Roher, A.E., Weiss, N., Kokjohn, T.A., Kuo, Y.M., Kalback, W., Anthony, J., Watson, D., Luehrs, D.C., Sue, L., Walker, D., Emmerling, M., Goux, W., Beach, T., 2002. Increased A beta peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer’s disease. Biochemistry 41, 11080–11090. Romeo, G.R., Kazlauskas, A., 2008. Oxysterol and diabetes activate STAT3 and control endothelial expression of profilin-1 via OSBP1. J. Biol. Chem. 283, 9595–9605. Royer, M.C., Lemaire-Ewing, S., Desrumaux, C., Monier, S., Pais de Barros, J.P., Athias, A., Néel, D., Lagrost, L., 2009. 7-ketocholesterol incorporation into sphingolipid/cholesterol-enriched (lipid raft) domains is impaired by vitamin E: a specific role for alpha-tocopherol with consequences on cell death. J. Biol. Chem. 284, 15826–15834. Rudkowska, I., 2010. Plant sterols and stanols for healthy ageing. Maturitas 66, 158–162. Rudolf, M., Curcio, C.A., 2009. Esterified cholesterol is highly localized to Bruch’s membrane, as revealed by lipid histochemistry in wholemounts of human choroid. J. Histochem. Cytochem. 57, 731–739. Ruiz, J.L., Fernandes, L.R., Levy, D., Bydlowski, S.P., 2013. Interrelationship between ATP-binding cassette transporters and oxysterols. Biochem. Pharmacol. 86, 80–88. Rujoi, M., Jin, J., Borchman, D., Tang, D., Yappert, M.C., 2003. Isolation and lipid characterization of cholesterol-enriched fractions in cortical and nuclear human lens fibers. Invest. Ophthalmol. Visual Sci. 44, 1634–1642. Russell, D.W., 2000. Oxysterol biosynthetic enzymes. Biochim. Biophys. Acta 1529, 126–135. Savouret, J.F., Antenos, M., Quesne, M., Xu, J., Milgrom, E., Casper, R.F., 2001. 7ketocholesterol is an endogenous modulator for the arylhydrocarbon receptor. J. Biol. Chem. 276, 3054–3059. Schenck, G.O., Gollnick, K., Neümuller, O.A., 1957. Photosensitized autoxidation of steroids preparation of steroid hydroperoxides by means of phototoxic photosentitizers. Liebigs Ann. 603, 46. Schmitz, G., Grandl, M., 2008. Lipid homeostasis in macrophages—implications for atherosclerosis. Rev. Physiol. Biochem. Pharmacol. 160, 93–125. Schmitz, G., Grandl, M., 2009. Endolysosomal phospholipidosis and cytosolic lipid droplet storage and release in macrophages. Biochim. Biophys. Acta 1791, 524–539. Schmitz, G., Müller, G., 1991. Structure and function of lamellar bodies, lipid-protein complexes involved in storage and secretion of cellular lipids. J. Lipid Res. 32, 1539–1570. Schreurs, B.G., Smith-Bell, C.A., Lemieux, S.K., 2013. Dietary cholesterol increases ventricular volume and narrows cerebrovascular diameter in a rabbit model of Alzheimer’s disease. Neuroscience 254, 61–69. Schroepfer Jr., G.J., 2000. Oxysterols: modulators of cholesterol metabolism and other processes. Physiol. Rev. 80, 361–554. Schweizer, R.A., Zürcher, M., Balazs, Z., Dick, B., Odermatt, A., 2004. Rapid hepatic metabolism of 7-ketocholesterol by 11beta-hydroxysteroid dehydrogenase type 1: species-specific differences between the rat, human, and hamster enzyme. J. Biol. Chem. 279, 18415–18424. Sharma, K., Sharma, N.K., Anand, A., 2014. Why AMD is a disease of ageing and not of development: mechanisms and insights. Front. Aging Neurosci. 6, 151. Shibata, N., Glass, C.K., 2010. Macrophages, oxysterols and atherosclerosis. Circ. J. 74, 2045–2051. Silva, J., Beckedorf, A., Bieberich, E., 2003. Osteoblast-derived oxysterol is a migration-inducing factor for human breast cancer cells. J. Biol. Chem. 278, 25376–25385. Silvente-Poirot, S., Poirot, M., 2014. Cancer. Cholesterol and cancer, in the balance. Science 343, 1445–1446. Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C.G., Simons, K., 1998. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc. Natl. Acad. Sci. U.S.A. 95, 6460–6464.

Slevin, M., Krupinski, J., Badimon, L., 2009. Controlling the angiogenic switch in developing atherosclerotic plaques: possible targets for therapeutic intervention. J. Angiogenes Res. 1, 4. Smiljanic, K., Vanmierlo, T., Djordjevic, A.M., Perovic, M., Loncarevic-Vasiljkovic, N., Tesic, V., Rakic, L., Ruzdijic, S., Lutjohann, D., Kanazir, S., 2013. Aging induces tissue-specific changes in cholesterol metabolism in rat brain and liver. Lipids 48, 1069–1077. Smith, L.L., 1987. Cholesterol autoxidation 1981–1986. Chem. Phys. Lipids 44, 87–125. Smith, L.L., Smart, V.B., Ansari, G.A., 1979. Mutagenic cholesterol preparations. Mutat. Res. 68, 23–30. Söderberg, M., Edlund, C., Kristensson, K., Dallner, G., 1990. Lipid compositions of different regions of the human brain during aging. J. Neurochem. 54, 415–423. Solomon, A., Leoni, V., Kivipelto, M., Besga, A., Oksengard, A., Julin, P., Svensson, L., Wahlund, L., Andreasen, N., Winblad, B., Soininen, H., Bjorkhem, I., 2009. Plasma levels of 24S-hydroxycholesterol reflect brain volumes in patients without objective cognitive impairments but not with Alzheimer’s disease. Neurosci. Lett. 462, 89–93. Spann, N.J., Glass, C.K., 2013. Sterols and oxysterols in immune cell function. Nat. Immunol. 14, 893–900. Sparks, D.L., Scheff, S.W., Hunsaker 3rd, J.C., Liu, H., Landers, T., Gross, D.R., 1994. Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp. Neurol. 126, 88–94. Stocker, R., Keaney Jr., J.F., 2004. Role of oxidative modifications in atherosclerosis. Physiology 84, 1381–1478. Svennerholm, L., Boström, K., Jungbjer, B., Olsson, L., 1994. Membrane lipids of adult human brain: lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years. J. Neurochem. 63, 1802–1811. Terlecky, S.R., Koepke, J.I., Walton, P.A., 2006. Peroxisomes and aging. Biochim. Biophys. Acta 1763, 1749–1754. Testa, G., Gamba, P., Badilli, U., Gargiulo, S., Maina, M., Guina, T., Calfapietra, S., Biasi, F., Cavalli, R., Poli, G., Leonarduzzi, G., 2014. Loading into nanoparticles improves quercetin’s efficacy in preventing neuroinflammation induced by oxysterols. PLoS One 9 (5), e96795. Thirumangalakudi, L., Prakasam, A., Zhang, R., Bimonte-Nelson, H., Sambamurti, K., Kindy, M.S., Bhat, N.R., 2008. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J. Neurochem. 106, 475–485. Titorenko, V.I., Terlecky, S.R., 2011. Peroxisome metabolism and cellular aging. Traffic 12, 252–259. Tosato, M., Zamboni, V., Ferrini, A., Cesari, M., 2007. The aging process and potential interventions to extend life expectancy. Clin. Interventions Aging 2, 401–412. Tousoulis, D., Kampoli, A.M., Tentolouris, C., Papageorgiou, N., Stefanadis, C., 2012. The role of nitric oxide on endothelial function. Curr. Vasc. Pharmacol. 10, 4–18. Trousson, A., Bernard, S., Petit, P.X., Liere, P., Pianos, A., El Hadri, K., Lobaccaro, J.M., Ghandour, M.S., Raymondjean, M., Schumacher, M., Massaad, C., 2009. 25Hydroxycholesterol provokes oligodendrocyte cell line apoptosis and stimulates the secreted phospholipase A2 type IIA via LXR beta and PXR. J. Neurochem. 109, 945–958. Vaya, J., Schipper, H.M., 2007. Oxysterols, cholesterol homeostasis, and Alzheimer disease. J. Neurochem. 102, 1727–1737. Vaya, J., Szuchman, A., Tavori, H., Aluf, Y., 2011. Oxysterols formation as a reflection of biochemical pathways: summary of in vitro and in vivo studies. Chem. Phys. Lipids 164, 438–442. Vejux, A., Kahn, E., Dumas, D., Bessède, G., Ménétrier, F., Athias, A., Riedinger, J.M., Frouin, F., Stoltz, J.F., Ogier-Denis, E., Todd-Pokropek, A., Lizard, G., 2005. 7Ketocholesterol favors lipid accumulation and colocalizes with Nile Red positive cytoplasmic structures formed during 7-ketocholesterol-induced apoptosis: analysis by flow cytometry FRET biphoton spectral imaging microscopy, and subcellular fractionation. Cytometry A 64, 87–100. Vejux, A., Guyot, S., Montange, T., Riedinger, J.M., Kahn, E., Lizard, G., 2009. Phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway are vitamin E inhibitable events associated with 7-ketocholesterol-induced apoptosis. J. Nutr. Biochem. 20, 45–61. Vejux, A., Lizard, G., 2009. Cytotoxic effects of oxysterols associated with human diseases: induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol. Aspects Med. 30, 153–170. Vejux, A., Samadi, M., Lizard, G., 2011. Contribution of cholesterol and oxysterols in the physiopathology of cataract: implication for the development of pharmacological treatments. J. Ophthalmol. 2011, 471947. Vrensen, G.F., 2009. Early cortical lens opacities: a short overview. Acta Ophtalmol 87, 602–610. Vuorinen, M., Solomon, A., Rovio, S., Nieminen, L., Kåreholt, I., Tuomilehto, J., Soininen, H., Kivipelto, M., 2011. Changes in vascular risk factors from midlife to late life and white matter lesions: a 20-year follow-up study. Dement. Geriatr. Cogn. Disord. 31, 119–125. Vurusaner, B., Gamba, P., Testa, G., Gargiulo, S., Biasi, F., Zerbinati, C., Iuliano, L., Leonarduzzi, G., Basaga, H., Poli, G., 2014. Survival signaling elicited by 27-hydroxycholesterol through the combined modulation of cellular redox state and ERK/Akt phosphorylation. Free Radical Med., http://dx.doi.org/10.1016/j.freeradbiomed.2014.07.026 (pii: Biol. S0891-5849(14)00343-8). Wang, J., Megha London, E., 2004. Relationship between sterol/steroid structure and participation in ordered lipid domains (lipid rafts): implications for lipid raft structure and function. Biochemistry 43, 1010–1018.


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Wang, S.F., Chou, Y.C., Mazumder, N., Kao, F.J., Nagy, L.D., Guengerich, F.P., Huang, C., Lee, H.C., Lai, P.S., Ueng, Y.F., 2013. 7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells. Biochem. Pharmacol. 86, 548–560. Wentworth Jr., P., Nieva, J., Takeuchi, C., Galve, R., Wentworth, A.D., Dilley, R.B., De Laria, G.A., Saven, A., Babior, B.M., Janda, K.D., Eschenmoser, A., Lerner, R.A., 2003. Evidence for ozone formation in human atherosclerotic arteries. Science 302, 1053–1056. Wood, W.G., Li, L., Müller, W.E., Eckert, G.P., 2014. Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. J. Neurochem. 129, 559–572. Woodruff-Pak, D.S., Agelan, A., Del Valle, L., 2007. A rabbit model of Alzheimer’s disease: valid at neuropathological, cognitive, and therapeutic levels. J. Alzheimers Dis. 11, 371–383.

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Yoon, J.H., Canbay, A.E., Werneburg, N.W., Lee, S.P., Gores, G.J., 2004. Oxysterols induce cyclooxygenase-2 expression in cholangiocytes: implications for biliary tract carcinogenesis. Hepatology 39, 732–738. Yuan, X.M., Li, W., Brunk, U.T., Dalen, H., Chang, Y.H., Sevanian, A., 2000. Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products. Free Radical Biol. Med. 28, 208–218. Zigman, S., Paxhia, T., Marinetti, G., Girsch, S., 1984. Lipids of human lens fiber cell membranes. Curr. Eye Res. 3, 887–896. Zonta, B., Minichiello, L., 2013. Synaptic membrane rafts: traffic lights for local neurotrophin signaling? Front. Synaptic Neurosci. 5 (9). Zuliani, G., Donnorso, M.P., Bosi, C., Passaro, A., Dalla Nora, E., Zurlo, A., Bonetti, F., Mozzi, A.F., Cortese, C., 2011. Plasma 24S-hydroxycholesterol levels in elderly subjects with late onset Alzheimer’s disease or vascular dementia: a case control study. BMC Neurol. 11, 121.


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The role of oxysterols in vascular ageing.

Intervening in ageing to prevent the diseases of ageing.

Effect of ageing on tactile transduction processes.

Molecular mechanisms of ageing and related diseases.

Involvement of tubular transport processes in nephrotoxicity.

Oxysterols.

Vascular Ageing and Exercise: Focus on Cellular Reparative Processes.

Free radicals: their involvement in disease processes.

Involvement of Kallikrein-Related Peptidases in Normal and Pathologic Processes.

Cardiovascular involvement in autoimmune diseases.

Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature.

Involvement of the liver in rheumatic diseases.

Involvement of endogenous retroviruses in prion diseases.

The involvement of microRNAs in neurodegenerative diseases.

Involvement of Arabidopsis HAC family genes in pleiotropic developmental processes.

Oxysterols and alcoholic liver disease.

Oxysterols and their cellular effectors.

Neuronal plasticity and ageing processes in the frame of the 'Red Queen Theory'.

Corneal involvement in systemic inflammatory diseases.

Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases.

Pulmonary involvement in the collagen vascular diseases.

Olfactory bulb involvement in neurodegenerative diseases.

Ocular involvement in primary immunodeficiency diseases.

MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.