Biochimica et Biophysica Acta 1841 (2014) 919–933

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Physiological regulation of lipoprotein lipase Sander Kersten Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Bomenweg 2, 6703HD Wageningen, The Netherlands

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Article history: Received 14 February 2014 Received in revised form 27 March 2014 Accepted 30 March 2014 Available online 8 April 2014 Keywords: Lipoprotein lipase Triglyceride-rich lipoproteins Apolipoproteins Angiopoietin-like proteins Adipose tissue Muscle

a b s t r a c t The enzyme lipoprotein lipase (LPL), originally identified as the clearing factor lipase, hydrolyzes triglycerides present in the triglyceride-rich lipoproteins VLDL and chylomicrons. LPL is primarily expressed in tissues that oxidize or store fatty acids in large quantities such as the heart, skeletal muscle, brown adipose tissue and white adipose tissue. Upon production by the underlying parenchymal cells, LPL is transported and attached to the capillary endothelium by the protein GPIHBP1. Because LPL is rate limiting for plasma triglyceride clearance and tissue uptake of fatty acids, the activity of LPL is carefully controlled to adjust fatty acid uptake to the requirements of the underlying tissue via multiple mechanisms at the transcriptional and post-translational level. Although various stimuli influence LPL gene transcription, it is now evident that most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins. These proteins can be divided into two main groups: the liver-derived apolipoproteins APOC1, APOC2, APOC3, APOA5, and APOE, and the angiopoietin-like proteins ANGPTL3, ANGPTL4 and ANGPTL8, which have a broader expression profile. This review will summarize the available literature on the regulation of LPL activity in various tissues, with an emphasis on the response to diverse physiological stimuli. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Many tissues rely on plasma triglycerides (TG) as an important source of fatty acids for subsequent oxidation and/or storage. Plasma TG are packaged into the TG-rich lipoproteins chylomicrons and very low-density lipoproteins (VLDL), which carry TG coming from the diet or synthesized in the liver, respectively. Utilization of plasma TG is dependent on lipoprotein lipase (LPL), which is attached to the capillary endothelium and catalyzes the hydrolytic cleavage of TG into fatty acids. LPL, originally referred to as clearing factor lipase [1], is produced by a limited number of cells that include (cardio)myocytes and adipocytes, and upon release by these cells is transported to the lumenal side of the capillary endothelium by the protein GPIHBP1 [2,3]. The luminal or endothelial LPL is referred to as the functional LPL pool, as it represents the portion of tissue LPL that is actively involved in plasma TG hydrolysis. Additionally, LPL is produced by macrophages and mammary gland secretory cells, and by fetal hepatocytes. Maturation of nascent LPL occurs in the endoplasmic reticulum and is promoted by the lipase maturation factor 1 [4]. The LPL enzyme is catalytically active as a dimer composed of two glycosylated 55 kDa subunits connected in a head-to-tail fashion by non-covalent interactions [5,6]. The human LPL gene consists of 9 exons and encodes a protein of 475 amino acids that can be divided into distinct structural and functional domains, including an N-terminal signal sequence, a catalytic domain, a ‘lid’ domain that covers the active site, and a C-terminal domain [7,8]. The catalytic triad for the active site is formed by the amino acids Ser159, Asp183, and His266. Recent evidence indicates that the 1388-1981/© 2014 Elsevier B.V. All rights reserved.

C-terminal portion of LPL, which mediates binding to heparin, is sufficient for binding to GPIHBP1 [9,10]. Accordingly, formation of the full length LPL homodimers is not required for interactions with GPIHBP1. Finally, LPL is subject to proteolytic cleavage by proprotein convertases at residue 297, which represents a potential regulatory mechanism [11]. The essential role of LPL in plasma TG clearance is illustrated by the severe hypertriglyceridemia in patients carrying mutations within the LPL gene [12]. Similarly, mice with a generalized deletion of LPL have markedly higher plasma TG levels at birth and die within 24 h due to an inability to process the milk lipids. At the time of death, LPL knockout (KO) pups are severely hypertriglyceridemic [13,14]. Tissue-specific deletions of LPL have further demonstrated the importance of LPL for local fatty acid uptake [15–17]. Deletion or disabling mutations in the GPIHBP1 gene also give rise to marked hypertriglyceridemia in mice and humans [3,18]. Conversely, transgenic mice overexpressing human LPL throughout the body show a 75% reduction in plasma TG [19]. Because LPL is a critical determinant of plasma TG clearance and resultant tissue uptake of fatty acids, the activity of LPL needs to be carefully regulated in order to match the rate of uptake of plasma TG-derived fatty acids to the needs of the underlying tissue and the ability of the tissue to dispose of the fatty acids, all while being confronted with huge fluctuations in the production of TG-rich lipoproteins. It will therefore come as no surprise that the activity of LPL is extensively regulated through multiple mechanisms, which primarily operate at the transcriptional and post-translational level. Regulation of DNA transcription is responsible for the upregulation of LPL gene expression and activity


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during (cardio)myogenesis and adipogenesis [20–22]. However, most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins. This review will summarize the current literature on regulation of LPL activity in various tissues, focusing on LPL regulation in response to physiological stimuli. 2. LPL-modulating proteins 2.1. Two groups of LPL modulating proteins As indicated above, physiological variation in LPL activity in various tissues is primarily achieved via post-translational mechanisms involving a number of extracellular proteins. These proteins can be divided into two main groups. The first group encompasses the apolipoproteins APOC1, APOC2, APOC3, APOA5, and APOE, which are mainly or exclusively produced in liver and are physically associated with a variety of lipoprotein particles including TG-rich lipoproteins. The second group includes several members of the family of angiopoietin-like proteins, specifically ANGPTL3, ANGPTL4 and ANGPTL8. A short description of the basic features of each of these LPL modulators is presented below. 2.2. Apolipoproteins C (APOC) Three members of the APOC family have been associated with modulation of LPL activity: APOC1, APOC2 and APOC3 [23]. All three APOC proteins have a molecular weight of around 8 kDa, are mainly produced in liver, and are physically associated with the major lipoprotein classes. Human genetic and in vitro studies have provided overwhelming support for a plasma TG-lowering effect of APOC2 via stimulation of LPL activity (summarized in [23]). Paradoxically, overexpression of the human APOC2 gene in mice leads to marked hypertriglyceridemia via impaired plasma TG clearance [24], suggesting that at higher concentrations APOC2 may inhibit LPL [23]. Several factors were shown to impact plasma APOC2 levels, including obesity/diabetes and several hypolipidemic drugs (summarized in [25]). However, these factors are primarily pathological or pharmacological in nature, suggesting that based on current knowledge APOC2 does not appear to be a major mediator of regulation of LPL activity in response to physiological stimuli, such as feeding/fasting, exercise and cold exposure. As opposed to APOC2, APOC1 and APOC3 inhibit LPL-dependent plasma TG clearance, as shown using transgenic mice overexpressing human and mouse APOC1 or C3 [26–28] or mice lacking APOC1 [29]. Recently, it was proposed that APOC1 and C3 inhibit LPL activity by displacement of the enzyme from TG-rich particles [30]. In addition, APOC1 and APOC3 may influence plasma lipoprotein metabolism via modulation of the activity of other enzymes involved in lipoprotein processing, as well as by altering the binding of APOC-containing lipoproteins to their receptors [23]. The plasma TG raising effect of APOC3 is supported by lower fasting and postprandial plasma TG levels in heterozygous carriers of a null mutation (R19X) in the APOC3 gene [31]. So far no APOC1 gene variants have been identified that give rise to reduced or elevated plasma TG levels in humans. Similar to APOC2, regulation of APOC3 production likely represents a key process in pharmacological modulation of plasma TG by fibrates [32], yet evidence is lacking for a major intermediary role of APOC3 in regulation of LPL activity by physiological events. 2.3. Apolipoprotein A5 (APOA5) Gene targeting studies in mice and genetic studies in humans have unequivocally established the plasma TG-reducing effect of APOA5 [33]. Indeed, loss of function mutations in the APOA5 gene give rise to early- or late-onset hyperchylomicronemia in humans [34–36]. The primary mechanism for TG-lowering by APOA5 is stimulation of LPL-mediated plasma TG clearance, although other mechanisms have

been suggested as well, including repression of VLDL synthesis via an intracellular mode of action and activation of receptor-mediated lipoprotein particle uptake in liver, either by serving as ligand for LDLreceptor family members or by facilitating binding of TG-rich lipoproteins to hepatic proteoglycan receptors [37]. How APOA5 stimulates LPL activity is not fully clear but it likely involves interactions between APOA5 and LPL, proteoglycans and GPIHBP1 [33]. So far there is little evidence that APOA5 production is altered as a key effector of physiological regulation of LPL activity. Whereas insulin downregulates APOA5 mRNA [38], glucose stimulates APOA5 gene expression [39]. The physiological relevance of these findings is probably limited, and they more likely contribute to dysregulation of plasma TG-clearance during insulin resistance and associated hyperinsulinemia. There is compelling data that stimulation of LPL-mediated plasma TG clearance by fibrates may be mediated by upregulation of APOA5, which has been shown to be a direct PPARα target gene in humans but not in mice [40–42]. APOA5 expression in human liver is correlated with CPT1A and PPARA mRNA, further indicating a role of PPARα in APOA5 regulation [43]. 2.4. Apolipoprotein E (APOE) Genetic variation at the APOE locus has been shown to impact cardiovascular disease risk in humans by altering plasma lipoprotein levels [44]. APOE is a 34.2 kDa component of TG-lipoproteins and is required for effective receptor-mediated hepatic uptake of their cholesterol-enriched remnants [45]. In contrast to APOA5 and the members of the APOC family, APOE is also produced in extra-hepatic cells and tissues, especially in macrophages. APOE elevates circulating levels of TG-rich lipoproteins, partly by reducing the LPL-mediated plasma TG clearance rate [46], and partly by stimulating hepatic VLDL-TG production [47,48]. The inhibitory action of APOE on LPL has been confirmed at the in vitro level [46,49]. Despite its importance as a major genetic determinant of plasma lipoprotein levels, there is little evidence that regulation of APOE production is responsible for physiological variations in LPL activity. 2.5. Angiopoietin-like protein 4 (ANGPTL4) ANGPTL4 is a 50 kDa protein that shows homology with angiopoietins and angiopoietin-like proteins. It is secreted by numerous cells including hepatocytes, adipocytes, (cardio)myocytes, endothelial cells, intestinal epithelial cells, and macrophages. Expression of ANGPTL4 is under transcriptional control of peroxisome proliferator-activated receptors (PPARs). Indeed, ANGPTL4 was originally cloned as a target gene of PPARα and PPARγ [50,51]. Depending on the specific tissue, ANGPTL4 mRNA levels are governed primarily by PPARα (hepatocytes) [50,52], PPARδ ((cardio)myocytes and macrophages) [53–56], or PPARγ (adipocytes) [50,51]. Consequently, expression of ANGPTL4 is highly stimulated in vitro and in vivo by free fatty acids, which are agonists for PPARs [53, 56–58]. Overexpression of ANGPTL4 in mice reduces local and post-heparin plasma LPL activity, thereby impairing plasma TG clearance and elevating plasma TG levels [59–61], whereas ANGPTL4 deletion increases LPL activity and reduces plasma TG concentrations [62]. Biochemical studies indicate that ANGPTL4 disables LPL at least partly by dissociating the catalytically active LPL dimer into inactive LPL monomers [63,64]. However, according to another study, instead of acting as a catalyst, ANGPTL4 functions as a conventional, non-competitive inhibitor that binds to LPL to prevent the hydrolysis of substrate as part of a reversible mechanism [65]. Recent evidence indicates that ANGPTL4 is a major physiological regulator of LPL activity under conditions of fasting and exercise [50, 62,66,67]. In addition to functioning as paracrine factor in tissues that express LPL, ANGPTL4 may also have an endocrine function via its production in tissues that do not express LPL, such as liver and intestine (Fig. 1). Consistent with a role of ANGPTL4 in lipolytic processing of

S. Kersten / Biochimica et Biophysica Acta 1841 (2014) 919–933


Fig. 1. Role of ANGPTLs in regulating plasma TG clearance. A) ANGPTL3 and ANGPTL8 serve as endocrine regulators of plasma TG clearance via their near exclusive production in liver (at least in human) and their LPL inhibitory action in peripheral tissues. B) Despite being produced in liver as well, ANGPTL4 functions primarily as a paracrine regulator of plasma TG clearance in peripheral tissues via local inhibition of LPL.

TG-rich lipoproteins in humans, a loss of function gene variant of ANGPTL4 is associated with reduced plasma TG levels [68]. Apart from its role as LPL inhibitor, which is mediated by the N-terminal portion and proteolytic fragment, ANGPTL4 is able to bind specific integrins via its C-terminal portion [69]. This mechanism of action of ANGPTL4 likely accounts for the modulating effect of ANGPTL4 on angiogenesis, endothelial migration & permeability, tumorigenesis, and renal glomerular function [70].

2.6. Angiopoietin-like protein 3 (ANGPTL3) ANGPTL3 was discovered as plasma lipid modulating factor via positional cloning in KK/San mice, a mutant strain of KK obese mice with markedly lower plasma free fatty acid (FFA) and TG levels [71]. In humans, mutations within the ANGPTL3 gene give rise to familial hypolipidemia, characterized by low plasma levels of total cholesterol, LDL-C, HDL-C, and triglycerides, or combinations thereof

Fig. 2. Summary of the main physiological stimuli regulating LPL activity in various tissues. The principal tissues characterized by a high level of LPL activity are shown.


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[72]. Furthermore, genome-wide association studies revealed that a common sequence variant at a locus near the ANGPTL3 gene is associated with plasma TG [73,74]. Studies using various animal models of ANGPTL3 overexpression or deletion have corroborated the stimulatory effect of ANGPTL3 on plasma TG, which is achieved by suppressing plasma TG clearance via inhibition of LPL activity [62,75,76]. The biochemical mechanism for LPL inhibition by ANGPTL3 is not fully clear but seems to be stoichiometrically distinct from LPL inhibition by ANGPTL4 [77,78]. Similar to the C-class of apolipoproteins, ANGPTL3 is produced exclusively in liver, where its expression is downregulated by leptin and insulin [79,80], and upregulated by the nuclear receptor LXR [81]. Because ANGPTL3 is produced by the liver only, which does not express LPL, it functions as an endocrine rather than paracrine factor. How regulation of ANGPTL3 synthesis in liver may contribute to tissue-specific regulation of LPL activity is unclear (Fig. 2). Recent data suggest that ANGPTL3 may cooperate with the related protein ANGPTL8 [82], which has a somewhat broader expression profile. 2.7. Angiopoietin-like protein 8 (ANGPTL8) ANGPTL8 (also referred to as RIFL, lipasin and betatrophin) is the most recently cloned member of the angiopoietin-like protein family. It has substantial homology with ANGPTL3 and ANGPTL4 but lacks the C-terminal fibrinogen-like domain that is characteristic for this family [83,84]. In mice ANGPTL8 is expressed mainly in liver and white and brown adipose tissue, with lower expression in kidney and intestine, while in humans expression appears to be specific for liver. Deletion of ANGPTL8 lowers plasma TG [85], whereas overexpression of ANGPTL8 raises plasma TG, likely by inhibiting LPL activity [82–84]. ANGPTL8 may inhibit LPL activity directly, or indirectly by promoting cleavage and activation of ANGPTL3 [82,84]. A variant of the human ANGPTL8 gene was associated with lower plasma LDL-C and HDL-C levels but not with plasma TG. Expression of ANGPTL8 in white adipose tissue and liver is markedly induced by refeeding, which is likely mediated by insulin [82–84], whereas expression of ANGPTL8 in brown adipose tissue is induced by cold [86]. Intriguingly, refeeding/insulin induces LPL activity in white adipose tissue, and cold exposure induces LPL activity in brown adipose tissue, raising questions about the physiological relevance and rationale of the observed ANGPTL8 regulation. 3. Regulation of LPL in adipose tissue 3.1. Lipid sources for adipocytes Adipocytes can acquire fatty acids for storage from three principal sources. The first source is de novo lipogenesis in adipocytes from glucose and acetate. The importance of this pathway is highly dependent on the animal species, and appears to be relatively insignificant in humans [87,88]. The second source is circulating FFA. Since circulating FFA mostly originate from adipose tissue, uptake of plasma FFA by adipose tissue essentially represents recycling of stored fatty acids and therefore does not contribute to net fat storage. The third and by far the most important source are circulating TG-rich lipoproteins in the form of VLDL and chylomicrons, which explains the high expression of LPL in adipose tissue. It should be noted that part of the fatty acids carried by VLDL may have arrived in the liver as FFA and their uptake by adipocytes can also be considered recycling of stored fatty acids. 3.2. Mechanism of nutritional regulation of plasma TG clearance in adipose tissue The adipose tissue continuously switches from being a net storage organ in the fed or post-prandial state to a net release organ in the fasted or post-absorptive state. Although LPL-mediated extracellular lipolysis and intracellular lipolysis mediated by the lipase trilogy ATGL–HSL–

MGL are never completely turned “off”, the flux through these pathways and the activities of the participating enzymes vary widely with nutritional status [89]. Clearance of TG-rich lipoproteins in adipose tissue is markedly elevated in the fed state compared to the fasted state [90], which is likely at least partly mediated by the presence and relative absence of insulin, respectively. Regulation of plasma TG-derived fatty acid uptake in adipose tissue occurs via three interrelated pathways that are described below. 3.2.1. Fatty acid spillover The first pathway influencing plasma TG-derived fatty acid uptake is fatty acid spillover, which describes the loss of plasma TG-derived fatty acids into the venous blood without being directly taken up by the underlying tissue. Although LPL is usually considered as a fat storage enzyme, it should be realized that a major proportion of the fatty acids released by LPL-catalyzed lipolysis are “lost” as spillover [91]. Estimates of the magnitude of fatty acid spillover vary but it is well accepted that spillover is higher in the fasted state [92], reaching estimates of 100%, compared to the post-prandial state. There is evidence that fatty acid spillover decreases with each successive meal and more profoundly affects chylomicrons compared with VLDL [93]. Many molecular details of the process of fatty acid spillover remain murky, mostly due to our lack of insight about the transport of fatty acids from the endothelial surface to the underlying adipocytes. For example, it could be envisioned that all fatty acids generated by plasma TG hydrolysis are taken up by adipocytes but that a portion leaves the cell again and ends up back in the circulation. If that is true, spillover may be controlled at the level of intracellular fatty acid esterification. Alternatively, it is possible that a portion of the released fatty acids never leaves the bloodstream or the endothelial cells in the first place, which implies possible regulation at the level of trans-endothelial transport of fatty acids. Although numerous lines of evidence corroborate the existence of fatty acid spillover, its purported magnitude is seemingly difficult to reconcile with the detailed and tissue-specific regulation of LPL activity [90]. Teusink and colleagues have proposed a model in which fatty acids released from LPL exchange locally with plasma FFA [90]. In this model, the purpose of LPL is to increase the local concentration of fatty acids close to the endothelium, which provides the driving force for the uptake of fatty acids into the underlying tissues. According to this scenario, a fatty acid spillover of close to 100% does not contradict with an important role of LPL-catalyzed TG clearance in local fatty acid uptake. 3.2.2. Regulation of LPL synthesis Early studies have indicated that fasting is associated with a pronounced decrease in LPL activity in adipose tissue (Fig. 2) [94,95], which may be mediated at the level of LPL production or via other mechanisms. LPL mRNA and protein production vary with nutritional status, with LPL expression being lowest after fasting [96,97]. Fluctuations in LPL mRNA during the feeding–fasting cycle may be related to changes in circulating glucocorticoids and insulin. Currently, the effects of glucocorticoids on adipose LPL mass and activity are rather ambiguous. Kern and colleagues found that the synthetic glucocorticoid dexamethasone decreased adipocyte LPL mRNA in vitro and in rats, resulting in corresponding changes in the LPL synthetic rate and LPL activity [98]. In line with these data, dexamethasone raised serum TG levels in mice [99]. By contrast, dexamethasone and cortisol increased LPL mRNA and activity in human adipose organ cultures, as did insulin [100,101]. Similarly, treatment of arthritic patients with prednisolone resulted in enhanced adipose LPL mass and activity [102]. Whether these differences in LPL response reflect species-specific differences is unclear. Insulin has been shown to play a central role in the postprandial response of adipose LPL activity [103]. Even though increases in LPL gene expression by insulin have been observed in adipocytes in vitro [104,105], changes in LPL mRNA probably only account for a small portion of the stimulation of LPL activity by insulin (see below).

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Another feeding-related mechanism that may result in changes in LPL mRNA is mediated by glucose-dependent insulinotropic polypeptide (GIP). It was shown that GIP increases LPL activity and mRNA in isolated human adipocytes via a pathway involving PI3-K activation, PKB, AMPK, TORC2, and CREB, and that is activated by resistin [106,107]. Whether GIP also plays a role in in vivo regulation of adipose LPL activity is unclear. Transcription of the LPL gene is stimulated during adipogenesis by the adipogenic transcription factor PPARγ [108], and is stimulated by fatty acids and other PPARγ agonists in differentiated adipocytes [109–111]. Fasting reduces expression of PPARγ in adipose tissue [112], providing a potential explanation for the reduction in LPL expression during fasting. Regulation of LPL expression by PPARγ in humans is supported by induction of LPL mRNA by rosiglitazone in human adipose tissue [113]. Another transcription factor that activates LPL gene transcription and that is reduced in adipose tissue upon fasting is SREBP-1 [114,115]. Whether SREBP-1 plays a role in in vivo regulation of LPL expression remains unclear. Taken together, it is clear that LPL expression in adipose tissue is governed via multiple transcription factors, yet it is unclear which of these pathways dominate regulation of LPL mRNA during feeding and fasting. 3.2.3. Post-translational regulation of LPL Fluctuations in adipose LPL mRNA and protein mass with feeding and fasting are relatively small compared to the amplitude of changes in LPL activity [66,116,117]. In fact, in some species LPL mRNA and activity move in opposite directions during fasting, with LPL activity decreasing and LPL mRNA or mass increasing [118,119], pointing to important regulation at the post-transcriptional and post-translational level. In humans, adipose LPL activity is markedly higher in the fasted state compared with the fed state [120]. Based on the pioneering work in the 1960s on the influence of transcriptional inhibitors on regulation of lipase activity in adipose tissue [121–123], Olivecrona was able to show that adipose LPL activity is primarily regulated during fasting at the post-translational level via a shift of extracellular LPL toward an inactive form [124], which is dependent on switching on a gene other than LPL [125,126]. The identity of this fasting-induced gene has been unequivocally determined to be ANGPTL4 [63,64], originally referred to as the fasting induced adipose factor FIAF [50]. The importance of ANGPTL4 in mediating nutritional regulation of LPL activity in adipose tissue is demonstrated by the observation that ANGPTL4 KO mice have elevated basal LPL activity and do not show any decrease in adipose LPL activity during fasting [66]. As a result, ANGPTL4 KO mice have markedly reduced plasma TG, to the point of being almost undetectable in fasted ANGPTL4 KO mice. In the same vein, injection of monoclonal antibodies against ANGPTL4 reduced plasma TG, elevated adipose LPL activity, and increased clearance of circulating TG into adipose tissue [127], whereas overexpression of ANGPTL4 reduces uptake of plasma TG-derived fatty acids into adipose tissue and raises plasma TG levels [63]. The importance of ANGPTL4 in governing LPL activity during feeding and fasting can easily be reconciled with the key role of insulin in regulating adipose LPL activity in vitro and in vivo [103,108,128]. Indeed, it was found that insulin potently suppresses ANGPTL4 mRNA in cultured adipocytes [129], and in rat adipose tissue [66], likely via the transcription factor FoxO1 [130], while raising adipose LPL activity. In humans, insulin reduces circulating ANGPTL4 levels, as revealed during hyperinsulinemic clamps [131]. Other proposed effects of insulin on LPL include stimulation of release of active enzyme from the cell and increased uptake of inactive extracellular LPL [132]. The suppressive effect of insulin on LPL activity was found to be mediated by phosphatidylinositol 3-kinase and mTOR-dependent signaling pathways [133]. Induction of adipose ANGPTL4 expression during fasting may be related to the loss of the inhibitory effect of insulin, and/or may be mediated by increased plasma FFA [58]. Plasma FFA not only are highly


potent activators of ANGPTL4 gene expression in adipocytes [134], but also cause marked inhibition of LPL activity [109,135], suggesting a link between elevated FFA and LPL activity via ANGPTL4. Other potential explanations for the increase in adipose ANGPTL4 mRNA during fasting are elevated circulating levels of glucocorticoids. It has been observed that dexamethasone directly stimulates ANGPTL4 transcription in adipose tissue and also raises serum TG levels in mice [99]. Whether induction of ANGPTL4 by glucocorticoids leads to modulation of adipose LPL activity remains to be demonstrated. Overall, these studies indicate that ANGPTL4 very likely represents the long sought-after factor that governs regulation of LPL activity during fasting and feeding in fat tissue and therefore can be considered a key determinant of fat storage. 3.3. Regulation of adipose LPL activity by hypoxia Since the 1960s it is known that high altitude simulation raises circulating TG levels [136] and that hypoxia may impact LPL activity [137]. In support of these data, plasma TG went up twofold in subjects during a 40 day simulated ascent of Mt. Everest [138]. While little information is available about the mechanisms underlying hypertriglyceridemia during chronic continuous hypoxia, it is plausible that the mechanisms are similar to those operating under conditions of chronic intermittent hypoxia. It was shown that chronic intermittent hypoxia inhibits plasma lipoprotein clearance and adipose LPL activity in association with upregulation of ANGPTL4 [139], which is a direct target of hypoxia inducible factor HIF1a in adipose tissue [140]. However, mice treated with monoclonal antibodies against ANGPTL4 still exhibited decreased uptake of TG-derived fatty acids into adipose tissue during chronic intermittent hypoxia, despite restoration of LPL activity, suggesting that inhibition of LPL is not the principal mechanism accounting for impaired TG tissue uptake in hypoxic mice [127]. 3.4. Regulation of adipose LPL activity by stress and catecholamines Both short-term and long-term stress elicited by immobilization lead to a pronounced decrease in LPL activity in adipose tissue, whereas immobilization causes an increase in plasma LPL activity [141]. The effect of immobilization stress, which is supposedly mediated by catecholamines, is very fast, leading to reciprocal changes in plasma and adipose LPL activity within minutes. The speed of the events suggest that stress leads to release of LPL into the bloodstream from its attachment to GPIHBP1 and/or heparan sulfate proteoglycans at the endothelial surface [142], but the mechanism underlying this effect remains unclear. Catecholamines are important mediators of the stress response and are known to directly impact LPL activity in adipose tissue. In vitro studies indicate that catecholamines reduce adipocyte LPL activity via downregulation of LPL gene transcription [105], reducing LPL translation by stimulating the interaction of a PKA-containing RNA binding complex to the LPL 3′UTR [143,144], inducing LPL protein degradation [132], and induction of ANGPTL4 mRNA (our unpublished observation). In brief, stress and catecholamines reduce adipose LPL activity via a number of complementary mechanisms. 3.5. Regulation of adipose LPL activity by LPS and TNFα Sepsis is a common surgical problem associated with profound changes in production of cytokines and hormones leading to marked metabolic perturbations including hypertriglyceridemia [145]. Development of hypertriglyceridemia may serve as an adaptive response to increase the capacity for binding and neutralization of endotoxins [146], and thereby protect against sepsis-associated complications [147]. Studies in rats have shown that endotoxin exposure causes hypertriglyceridemia by reducing plasma TG clearance, pointing to a potential role of LPL [148]. Compelling evidence indicates that endotoxins decrease LPL activity in adipose tissue [148–151], and in skeletal muscle and heart [149,151,


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152]. The effect of endotoxin is conveyed via TNFα [153], which has been consistently found to reduce LPL activity in vivo and in vitro [154–158]. TNFα represses LPL activity by downregulating LPL transcription and thereby LPL mRNA, and furthermore a more recent study indicates that TNFα upregulates a gene whose product inactivates extracellular LPL [159]. So far the identity of the TNFα-induced LPL inhibitor remains elusive, but it probably does not represent ANGPTL4, as ANGPTL4 expression was not altered by TNFα in 3T3-L1 adipocytes [160]. 4. Regulation of LPL in skeletal muscle 4.1. Lipid sources for myocytes Myocytes acquire fatty acids from plasma FFA and circulating TG-rich lipoproteins [90]. The absolute and relative importance of each of these two sources is influenced by a variety of factors, with nutritional status and physical exercise being the dominant ones. In addition, fuel use is determined by fiber type [161]. Type 1 oxidative slow-twitch fibers are heavily reliant on lipid fuels, whereas Type IIB glycolytic fast twitch fibers prefer glucose and glycogen. When fatty acid uptake exceeds the rate of fatty acid oxidation, fatty acids can be stored as TG in the muscle within lipid droplets, which is referred to as intra-myocellular lipid. Intra-myocellular lipid is believed to serve as a readily available fuel during endurance exercise [162]. 4.2. Nutritional regulation of skeletal muscle LPL activity Substantial fatty acid spillover also occurs in skeletal muscle, although it has been suggested that the extent of fatty acid spillover is less in muscle than in adipose tissue [163]. The same considerations that have been expressed for spillover in adipose tissue also apply to spillover in muscle and will therefore not be further elaborated on here. In contrast to adipose tissue, where LPL is mostly extracellular, in skeletal muscle a much higher proportion of LPL is intracellular. Accordingly, changes in total LPL activity in skeletal muscle more closely reflect total LPL mass rather than functional LPL directly involved in endothelial hydrolysis of TG-rich lipoproteins, which explains why in general a relatively close correspondence is found between changes in muscle LPL mRNA and total LPL activity. A limited number of studies have employed heparin perfusion or prepared heparin eluates from fresh muscle tissue to determine the activity of the functional LPL pool [164, 165]. Unfortunately, the technique is not straightforward and its use has not been widespread. In contrast to LPL in adipose tissue, most studies indicate that fasting and starvation raise total LPL activity in skeletal muscle [97,117,166], the extent of which is somewhat dependent on the type of muscle studied [167]. Results are not all consistent as Eckel and colleagues reported a significantly higher muscle heparin-releasable LPL activity in human subjects in the fed state compared with the fasting state [120]. At the mRNA level, LPL was found to be increased by fasting in skeletal muscle in mice [168] and humans [169] (our unpublished observations). Little is known about the molecular mechanisms involved in governing muscle LPL during fasting, including regulation of the endothelial LPL pool. In contrast to its effect in adipose tissue, infusion of insulin decreased skeletal muscle LPL activity in humans [128]. It has been suggested that the increase in skeletal muscle LPL activity and mRNA during fasting is mediated by an increase in LPL transcription [170], and is driven by the transcription factor Foxo1 [171]. Similar to the situation in adipose tissue, expression of the LPL inhibitor ANGPTL4 is markedly increased during fasting in mouse and human skeletal muscle [63,67,160], likely via elevated plasma FFA [56, 58], which may offset any increase in LPL mRNA and/or mass and may thereby lead to decreased functional LPL activity. In vitro in cultured myocytes, fatty acids and other agonists of PPARδ and RXR cause reciprocal induction of ANGPTL4 mRNA and reduction in heparinreleasable LPL activity, respectively [67,172,173], suggesting that fatty

acids may regulate LPL activity in muscle during fasting via PPARδ/ RXR and ANGPTL4. In summary, whereas LPL mRNA and total activity in skeletal muscle appear to be increased upon fasting, there is no evidence that functional LPL activity is elevated as well. The marked induction in expression of ANGPTL4 during fasting may be predicted to lead to a decrease in functional LPL activity. In terms of nutritional physiology, it can be argued that LPL activity in muscle should increase during fasting to allow greater reliance on lipid fuels at the expense of carbohydrate. Alternatively, it stands to reason that the increased flux of plasma FFA into muscle during fasting should be compensated by decreased uptake of plasma TG-derived fatty acids in order to limit fasting-induced lipid overload, which would argue for a decrease in LPL activity. 4.3. Regulation of skeletal LPL activity by acute exercise One of the unique features of skeletal muscle is that it exhibits extreme metabolic plasticity, as shown by its ability to adjust fuel use depending on the metabolic circumstances, a property referred to as metabolic flexibility. In addition, skeletal muscle is able to massively increase the rate of ATP synthesis during physical exercise. Initiation of exercise commands immediate adjustments in fuel provision to the muscle to permit sufficient ATP generation, including changes in the supply and uptake of lipid fuels. Numerous studies in humans and rodents have demonstrated that a single bout of physical exercise leads to a marked increase in LPL activity, protein, and mRNA in the exercising muscle [97,164,174–179]. The physiological rationale behind the rapid exercise-induced stimulation of LPL activity is to increase the supply of fatty acids to the cell for subsequent oxidation to CO2 and H2O and generate ATP. In addition, it may promote the post-exercise restoration of intramyocellular TG that have been used during exercise. Currently, there is a scarcity of information on the physiological and molecular mechanisms involved in the induction of muscle LPL expression by acute exercise. One possibility is via elevated catecholamines, which were found to stimulate skeletal muscle LPL activity in humans [180]. In agreement with this notion, chronic β-adrenergic activation stimulated muscle LPL activity in rats [181]. A role of contractioninduced signaling molecules such as AMPK can be hypothesized but concrete evidence is lacking. Recently, we found that ANGPTL4 is selectively induced during exercise in non-exercising muscle compared with exercising muscle, which is explained by the opposing effect of plasma FFA (stimulatory, via PPARδ) and AMPK (inhibitory) on ANGPTL4 gene expression [67]. It was suggested that selective induction of ANGPTL4 in non-exercising muscle reduces local fatty acid uptake presumably to prevent fat overload, while directing fatty acids to the active skeletal muscle as fuel. 4.4. Regulation of skeletal LPL activity by exercise training It is well established that regular exercise lowers circulation TG levels [182], suggesting that exercise training, representing a series of incremental training bouts, may increase muscle LPL activity. Consistent with this notion, numerous studies in rodents have shown that exercise training significantly increases muscle heparin releasable LPL activity, LPL mass, and LPL mRNA (Fig. 2) [164,165,175,183]. Cross-sectional and intervention studies have confirmed that endurance exercise training stimulates LPL activity in humans [184–186]. Conversely, detraining leads to a decrease in muscle LPL activity, with variable changes in LPL immunoreactive mass and mRNA levels, depending on the duration of inactivity [187,188]. The increase in muscle LPL abundance following exercise training can be considered an adaptive change that promotes fuel supply to the muscle and thereby may promote oxidative capacity. Conversely, the decrease in LPL activity in inactive muscle may serve as an adaptive mechanism to minimize unnecessary lipid accumulation and potential lipotoxicity [187]. How exercise training and/or chronic inactivity lead

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to alterations in LPL activity and mRNA is unclear. Hamilton and colleagues found that the decrease in rat muscle heparin-releasable LPL activity upon physical inactivity was independent of a change in LPL mRNA concentration, and concluded that inactivity results in upregulation of a gene encoding an LPL inhibitor, the identity of which remains obscure [187]. 5. Regulation of LPL in heart 5.1. Lipid sources for heart Cardiac contractility depends on the adequate delivery of oxygen and energy substrates to the heart followed by oxidation of energy substrates to yield ATP. The energy requirements of the contracting heart are mainly met by fatty acid oxidation, with the remainder of energy coming from oxidation of glucose and lactate [189,190]. Although fatty acids are thus essential for cardiac contractility, excessive uptake of fatty acids causes lipid overload or lipotoxicity and may disturb cardiac function, possibly leading to cardiomyopathy [191]. Most of the fatty acids taken up and oxidized by the heart are derived from LPL-dependent hydrolysis of circulating TG-rich lipoproteins [90]. In contrast to skeletal muscle, circulating FFA are of relatively minor importance as fuel for the heart. Accordingly, LPL activity in the heart needs to be carefully regulated to match plasma TG hydrolysis and consequent lipid uptake into cardiomyocytes with cardiac contractility and the cellular requirement for ATP. Loss of LPL specifically in the heart is associated with elevated plasma levels and impaired clearance of TG-rich lipoproteins and a compensatory increase in glucose uptake and glucose oxidation, which cannot prevent age-related cardiac dysfunction as revealed by decreased fractional shortening and interstitial and perivascular fibrosis [192]. 5.2. Nutritional regulation of cardiac LPL activity As in skeletal muscle, a very high proportion of LPL in heart is intracellular and cannot be released by heparin, which should be taken into account when interpreting total LPL activity data. Early investigations have demonstrated that fasting causes an increase in heparin releasable LPL activity in the heart (Fig. 2) [193,194], which has been corroborated in several more recent studies [195–197], with some exceptions [116]. In contrast, insulin decreases cardiac heparinreleasable LPL activity [198]. Similar to what is observed in adipose tissue, fasting provokes a more pronounced change in cardiac heparinreleasable LPL activity compared with total cardiac LPL activity [193, 199,200]. Heparin-agarose chromatography of heparin-released LPL indicated that the proportion of active dimeric LPL is higher in the fasted state than in the fed state. Transcription inhibition by actinomycin D increased heparin-releasable LPL activity in hearts of fed rats and increased the relative abundance of active LPL [201]. Accordingly, it has been hypothesized that feeding is associated with the production of an LPL inhibitor that converts active LPL into inactive LPL [201]. An attractive candidate is ANGPTL4, which shows increased expression in the heart after an oral fat load [53]. Overexpression of ANGPTL4 in the heart reduces cardiac heparin-releasable LPL activity. In addition, cardiac ANGPTL4 overexpression raises circulating TG levels, lowers cardiac TG levels and causes left-ventricular dysfunction [60]. Expression of ANGPTL4 in the heart is induced by dietary fatty acids via the transcription factor PPARδ and is likely part of a feedback mechanism aimed at limiting fatty acid uptake and protecting against cardiac overload and lipotoxicity [53]. Intriguingly, expression of ANGPTL4 was also found to be increased in the fasted state relative to the ad libitum fed state [63]. Accordingly, it is somewhat doubtful whether ANGPTL4 is responsible for the relative inactivation of cardiac LPL in the fed state. Intracellular factors that impact LPL activity in cardiomyocytes include PPARα and AMPK. Activation of PPARα in cultured cardiomyocytes using


synthetic or endogenous agonists gives rise to decreased total cellular LPL activity, which is mediated by post-transcriptional and post-translational mechanisms, presumably involving ANGPTL4 as cardiac PPARα target [202,53]. Conversely, activation of AMPK leads to increased heparinreleasable LPL activity in heart, whereas AMPK inhibition causes a marked decrease in LPL activity [199,203]. Finally, cold exposure, which increases energetic demands on the heart, was found to increase total and heparinreleasable LPL activity in the rat heart [204,205]. The molecular mechanisms involved in modulation of cardiac LPL activity by AMPK and cold remain to be elucidated. 6. Regulation of LPL in brown adipose tissue 6.1. Lipid sources for brown adipocytes The physiological function of brown adipose tissue is to generate heat and maintain body temperature as part of cold-adaptive thermogenesis [206]. In many animal species, cold provokes chronic expansion of BAT mass as well as changes in BAT morphology and specific enzymatic activity, together leading to a marked increase in total thermogenic capacity. Recent studies in human subjects indicate cold-induced hypermetabolic activity in multifocal regions along the neck, supraclavicular regions, mediastinum, and paraspinal regions, suggesting adult human possess BAT or a BAT-like tissue [207–210]. BAT is a highly oxidative tissue and therefore requires the provision of large amounts of glucose and lipid fuels [206]. A major source of lipid for brown adipocytes are fatty acids generated via intracellular lipolysis of locally stored TG. The second lipid source are plasma FFA originating from lipolysis in white adipose tissue. The third lipid source and most relevant to the present article are circulating TG-rich lipoproteins in the form of VLDL and chylomicrons, which explains the high expression of LPL in brown adipocytes. The importance of LPL in uptake of TG-derived fatty acids in BAT was recently demonstrated using adipocyte-specific LPL KO animals [211,212]. 6.2. Regulation of LPL activity in bat by cold Concomitant with the gradual expansion of the brown adipose tissue mass in rats and mice, cold exposure leads to a marked increase in total LPL activity in BAT (Fig. 2) (expressed per depot) [213,214], as well as an increase in post-heparin plasma LPL activity [204]. As a consequence, cold increases extraction of plasma TG-derived fatty acids into BAT and reduces plasma TG levels [214,215]. In addition, cold exposure increases specific LPL activity in BAT [216–218]. Induction of specific LPL activity by cold is most prominent during the early hours and then declines to reach a level that still significantly exceeds baseline LPL activity [219]. The increase in LPL activity is mediated by a transcription and translation-dependent mechanism, is paralleled by a similar increase in LPL mRNA, and can be mimicked by β-adrenergic agonists, suggesting that β-adrenergic stimulation is the key mechanism for LPL induction during cold [181,215,217,219–221]. Subsequent experiment in cultured brown adipocytes from rat showed that β3-adrenergic agonists but not β1- or β2-adrenergic agonists directly stimulate LPL mRNA [222]. Surprisingly, β-adrenergic stimulation tended to decrease LPL mRNA in cultured brown adipocytes from mouse [221]. In contrast to mice and especially rats, hamsters show a decrease in size of the BAT depot following acute and chronic cold exposure, concurrent with a marked increase in LPL activity [223]. The increase in LPL activity upon cold exposure clearly exceeds the increase in LPL protein and/or mRNA, suggesting a disproportion increase in the active fraction of LPL [220]. Cold-induced activation of LPL activity in BAT in hamsters is not dependent on T3 [224], and similar to rats and mice can be reproduced by β-adrenergic activation [225]. In summary, cold markedly stimulates LPL activity in BAT, causing a reduction in plasma TG and potentially leading to alterations in other lipoproteins species, feeding speculations that BAT may be a fruitful


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target for the treatment of hypertriglyceridemia and other disorders in plasma lipoproteins [215]. 6.3. Regulation of LPL activity in bat by other factors Other factors that have been shown to influence LPL in BAT include PPARγ agonists. PPARγ activation increases specific LPL activity in BAT of rats, concomitant with a huge increase in BAT mass [226], leading to a marked increase in uptake of TG-derived fatty acids in BAT [227, 228]. Studies in fetal rat primary brown adipocytes indicate that PPARγ activation increases LPL mRNA and activity [229], suggesting that PPARγ stimulates LPL activity in vivo via direct transcriptional regulation of LPL [111]. The impact of fasting on LPL activity in BAT remains unclear. Whereas short term fasting increased specific LPL activity in BAT in rats [216], 3 days of fasting decreased total LPL activity, which returned to control values by day 3 of refeeding [230]. Similar to in white adipose tissue, insulin induced LPL activity in BAT [231]. 7. Regulation of LPL in macrophages 7.1. Role of lipoprotein lipase in macrophages It has long been recognized that macrophages have the ability to hydrolyze TG within chylomicrons via lipase activity and oxidize or re-esterify the released fatty acids [232–235]. The TG-depleted and cholesterol-enriched remnant is subsequently taken up by macrophages via an APOE-mediated process [236]. Most of the published studies on LPL in macrophages have addressed the potential impact of LPL on foam cell formation and atherogenesis, showing expression of LPL in macrophages and foam cells in atherosclerotic plagues [237, 238], and a stimulatory role of LPL in foam cell formation from TG-rich lipoproteins or oxidized LDL [239,240]. Consistent with these data, various types of gene targeting studies indicate stimulation of in vivo atherosclerosis by macrophage LPL. Indeed, macrophage-specific overexpression of LPL promotes the formation of atherosclerotic lesions and accumulation of macrophage-derived foam cells [241–244], which occurs in the absence of any changes in circulating lipoproteins, whereas the opposite is observed in macrophage specific LPL KO mice [245,246]. Given the link between LPL and atherogenesis, data on regulation of LPL in macrophages have been mainly viewed in relation to its potential impact on atherosclerosis. Remarkably, the basic question why macrophages abundantly express LPL and what may be the role of LPL in fuel provision to the macrophage or other macrophage functions has remained unanswered. It has been proposed that fatty acids released upon macrophage LPL-catalyzed hydrolysis of TG are an important fuel for macrophages when glucose availability is limited and during periods of intense metabolic activity, such as phagocytosis [247]. In agreement with this notion, proliferating macrophages secrete large amounts of LPL activity, whereas in nonproliferating, quiescent cells, LPL activity is much lower [248]. A role of LPL in fuel provision in macrophages automatically raises the question why none of the other leukocytes including dendritic cells express LPL. A complicating factor is that the TG-rich lipoproteins that serve as substrate for LPL-mediated hydrolysis cannot easily cross the endothelium and thus hardly get into direct contact with tissue macrophages. An exception may be the mesenteric lymph nodes, where extremely high concentrations of chylomicrons directly pass macrophages in the subscapular sinus of the mesenteric lymph node [55]. One could postulate that macrophages in mesenteric lymph nodes survey newly synthesized chylomicrons for immunogenic lipids via LPLmediated lipolysis and present them to adjacent natural killer T cells, thereby conferring a major immunological role onto LPL. Overall, the limited understanding of the role of macrophage LPL in immunity hampers interpretation of the functional implications of macrophage LPL regulation by a variety of stimuli.

7.2. Regulation of macrophage LPL activity by inflammatory parameters A major portion of the LPL secreted by macrophages remains associated with the cell membrane and can be released by heparin. This heparin-releasable secreted LPL activity has been the primary output parameter in most studies on LPL regulation. The level of secreted LPL activity is highly dependent on the activation state of macrophages. Fully activated macrophages obtained from Corynebacterium parvum-injected mice secrete very low levels of LPL activity when compared with unstimulated macrophages, while thioglycollateelicited inflammatory macrophages secrete much higher levels of LPL activity [249,250]. Lipopolysaccharide (LPS) inhibits secreted LPL activity, which is likely mediated at the level of LPL gene transcription (Fig. 2) [250–253]. The inhibitory effect of LPS may be partially conveyed by numerous cytokines released in response to LPS, including TNFα, interferon γ and IL-1β [254]. Inhibition of secreted LPL activity by TNFα has been observed in mouse peritoneal macrophages but not in J774.1, BMDM and human monocyte-derived macrophages [252,253,255]. Interferon γ decreases macrophage LPL at least in part via a reduction in LPL synthesis and gene transcription, possibly via CK2 and PI3K signaling and regulation of Sp1/Sp3 binding [256,257]. Another cytokine that has been shown to inhibit LPL activity is transforming growth factor β [258], whereas macrophage colony-stimulating factor, C-reactive protein, platelet-derived growth factor and elevated concentrations of hydrogen peroxide (H2O2) were found to stimulate secreted LPL activity and/or LPL mRNA [259–262].

7.3. Regulation of macrophage LPL activity by nuclear hormone receptors Several studies have found a marked suppression of secreted LPL activity by the glucocorticoid receptor agonist dexamethasone in mouse macrophages [263–265]. Interestingly, dexamethasone stimulated LPL transcription in human THP-1 and monocyte-derived macrophages [266], suggesting a possible species difference in regulation of LPL by glucocorticoids. Agonists for PPARα and PPARγ increase LPL mRNA expression in human macrophages [267,268]. Interestingly, Staels and colleagues reported that PPAR activators decrease secreted LPL mass and enzyme activity [267], whereas Renier observed an increase in the same parameters [268]. Activation of PPARδ did not affect LPL mRNA in macrophages but markedly reduced secreted LPL activity, which is likely caused by concomitant induction of ANGPTL4 [269,270]. Similarly, upregulation of ANGPTL4 likely explains the reduction in secreted LPL activity upon incubation of macrophages with oleic acid and TG-rich lipoproteins [271]. Another nuclear receptor that has been suggested to be involved in LPL regulation is LXR, which is activated by oxysterols. Prolonged treatment with the synthetic LXR agonist T0301719 stimulated LPL expression in peritoneal macrophages by about 2-fold [272]. In contrast, the natural LXR agonist 25-hydroxycholesterol reduced LPL mRNA and secreted LPL activity in human monocyte-derived macrophages [273]. The same response was observed for 7 β-hydroxycholesterol, which is not a LXR agonist, arguing against an involvement of LXR. Incubation of human monocytes-macrophages with highly oxidized LDL, which is enriched with oxysterols, also decreased LPL mRNA and secretion [274]. Based on this limited information, the role of LXR in regulation of macrophage LPL by oxLDL and oxysterols remains unclear. Other factors that have been shown to influence LPL in macrophages include cAMP activators, which potently repress LPL activity [263,275, 276], and glucose, which causes marked upregulation of LPL mRNA expression and immunoreactive mass [277]. Insulin has no effect on LPL secretion, even though peritoneal macrophages isolated from insulin-deficient mice secreted 70% less LPL activity than control mice [265,278].

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8. Regulation of LPL in other tissues 8.1. LPL activity in the lung In addition to its well established expression and function in adipose tissue, muscle, and macrophages, LPL enzyme activity has been detected in other tissues and cells, including lung, lactating mammary gland, brain, and kidney. Expression of LPL in lung is related to the abundance of LPL-expressing macrophages [279]. It has been proposed that LPL activity in lung cancer tissue predicts shorter survival in patients with nonsmall cell lung cancer [280]. Based on its macrophage origin, it can be speculated that LPL activity in lung is primarily under control of inflammatory mediators, although no actual data are available. 8.2. LPL activity in the kidney In contrast to adipose tissue and heart, LPL activity in kidney exhibits very pronounced inter-species variation, with highest activity in mink, followed by Chinese hamster and mouse, and low activity in rat and guinea pig [281]. Food deprivation decreases LPL activity in kidney without corresponding changes in LPL mRNA or mass via a mechanism reliant on changes in gene transcription. LPL in kidney has been located to the mesanglial cells [282], where it promotes VLDL-induced lipid accumulation [283]. In addition, LPL has been located to tubular epithelial cells and the renal vascular endothelium [197,281,284]. 8.3. LPL activity in mammary gland LPL activity is known to be highly elevated in the lactating mammary gland to extract circulating TG for incorporation into milk fat. Both secretory mammary epithelial cells and interstitial cells located in the connective tissue adjacent to mammary alveoli, which may represent regressed lipid-depleted mammary adipocytes, have been suggested to serve as source of LPL in the lactating mammary gland [284,285]. In line with (residual) adipocytes being the primary carrier of LPL activity, adipocyte and mammary gland LPL activity respond in the same manner to metabolic stimuli. Indeed, experimental hyperinsulinemia induced LPL activity and mRNA in mammary gland of rats [286]. Conversely, fasting decreased milk and heparin-releasable LPL activity in mouse/ rat mammary gland, whereas cell-associated LPL was less affected and LPL mRNA remained unaltered, pointing to a post-transcriptional mechanism [287,288]. Prolactin, which coordinates milk production during lactation, has been suggested to be a major stimulator of LPL activity in the mammary gland [289]. Indeed, prolactin stimulated heparin-releasable LPL activity and LPL mRNA in cultured mammary tissues derived from midpregnant mice [290]. However, Da Costa and Williamson did not find a major effect of prolactin and instead point to insulin as key hormone governing mammary gland LPL activity and plasma TG clearance in rats [291]. No data are available about the potential mechanisms underlying insulin and prolactin action on LPL. 8.4. LPL activity in the brain Due to the blood brain barrier, circulating lipoproteins are unable to reach the brain, except perhaps for small HDL particles. Most of the lipoproteins inside the central nervous system are likely produced by astrocytes. Currently, many aspects of lipoprotein metabolism in the brain remain enigmatic, including the role of neurons in regulation of lipoprotein metabolism and the major functions of lipoproteins in the brain [292]. Interestingly, LPL activity has also been found in the brain, in particular in the hypothalamus, cortex, cerebellum, and midbrain of adult rats [293]. In situ hybridization revealed strong LPL mRNA signals in pyramidal neurons of the rat hippocampus, the brain cortex and in the intermediate lobe of the pituitary gland [294], while another study also found


high levels of LPL activity and mRNA in the caudal spinal cord and in Purkinje cells of the cerebellum [295]. Uptake and incorporation of fatty acids from labeled TG demonstrated the functionality of LPL in cultured brain cells, as well as in vivo in the CNS in general [293,295]. LPL in brain has been associated with Alzheimer disease at the cellular and genetic level, but results obtained are too inconsistent to reach firm conclusions. Recent evidence indicates that LPL in brain plays a role in regulation of food intake and in provision of essential fatty acids [296]. Specifically, neuron-specific LPL-deficient mice were hyperphagic and obese. In contrast, genetic or chemical inactivation of LPL specifically in the hippocampus in rodents did not affect food intake but promoted body weight gain via decreased locomotor activity and energy expenditure, concomitant with increased parasympathetic tone [297]. In all brain regions tested except the hippocampus, LPL activity was either decreased by fasting, or showed no change [293,298,299]. In rat hippocampus LPL activity was increased by fasting [298]. Since lack of LPL leads to increased food intake, it can be hypothesized that fasting may exert an orexigenic effect partly via reduced LPL activity. No additional information is available about regulation of LPL activity in various brain regions by other (physiological) stimuli. 9. Conclusion The cellular uptake of fatty acids needs to be adjusted to local requirements and thus highly fluctuates between different tissues and between different physiological and nutritional states. By catalyzing the hydrolysis of circulating TG, LPL serves as one of the central gatekeepers that controls local fatty acid uptake. Consistent with this important function, the activity of LPL is subject to multiple regulatory mechanisms via a number of regulatory proteins. Some of these mechanisms are locally driven and, for instance, may serve to limit uptake of fatty acids from TG-rich lipoproteins when other fuels such as plasma FFA are plentiful. Others are effectors of hormonal signals that coordinate fuel metabolism and fatty acid uptake between various tissues, depending on the physiological and nutritional state. The last decade has witnessed the emergence of a novel class of proteins named ANGPTLs whose primary function is to inhibit LPL activity. These ANGPTLs likely turn out to represent the elusive mediators in the local and hormonal control of LPL activity and resultant fatty acid uptake that were predicted from more ancient studies. Indeed, regulation of ANGPTL4 was shown to be responsible for the reduction in LPL activity in white adipose tissue during fasting. Nevertheless, the current picture is still very far from complete. There is a clear need for appropriate experiments to try to demonstrate the role of each of these LPL modulators in the regulation of LPL activity in response to various local, hormonal and also pharmacological cues. Overall, the multitude of regulatory influences converging onto LPL illustrates the essential role of LPL-mediated plasma TG hydrolysis in cellular lipid homeostasis. References [1] E.D. Korn, Clearing factor, a heparin-activated lipoprotein lipase. I. Isolation and characterization of the enzyme from normal rat heart, J. Biol. Chem. 215 (1955) 1–14. [2] B.S. Davies, A.P. Beigneux, R.H. Barnes II, Y. Tu, P. Gin, M.M. Weinstein, C. Nobumori, R. Nyren, I. Goldberg, G. Olivecrona, A. Bensadoun, S.G. Young, L.G. Fong, GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries, Cell Metab. 12 (2010) 42–52. [3] A.P. Beigneux, B.S. Davies, P. Gin, M.M. Weinstein, E. Farber, X. Qiao, F. Peale, S. Bunting, R.L. Walzem, J.S. Wong, W.S. Blaner, Z.M. Ding, K. Melford, N. Wongsiriroj, X. Shu, F. de Sauvage, R.O. Ryan, L.G. Fong, A. Bensadoun, S.G. Young, Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons, Cell Metab. 5 (2007) 279–291. [4] M. Peterfy, O. Ben-Zeev, H.Z. Mao, D. Weissglas-Volkov, B.E. Aouizerat, C.R. Pullinger, P.H. Frost, J.P. Kane, M.J. Malloy, K. Reue, P. Pajukanta, M.H. Doolittle, Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia, Nat. Genet. 39 (2007) 1483–1487.


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Physiological regulation of lipoprotein lipase.

The enzyme lipoprotein lipase (LPL), originally identified as the clearing factor lipase, hydrolyzes triglycerides present in the triglyceride-rich li...
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