Lipoprotein lipase: from gene to atherosclerosis.

Atherosclerosis 237 (2014) 597e608

Contents lists available at ScienceDirect

Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Lipoprotein lipase: From gene to atherosclerosis Yuan Li a, 1, Ping-Ping He a, e, 1, Da-Wei Zhang b, Xi-Long Zheng c, Fracisco S. Cayabyab d, Wei-Dong Yin a, *, Chao-Ke Tang a, * a Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Discovery, Life Science Research Center, University of South China, Hengyang, Hunan 421001, China b Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada c Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The Cumming School of Medicine, The University of Calgary, Health Sciences Center, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada d Department of Surgery, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada e School of Nursing, University of South China, Hengyang, Hunan 421001, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 May 2014 Received in revised form 13 October 2014 Accepted 13 October 2014 Available online 18 October 2014

Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and responsible for catalyzing lipolysis of triglycerides in lipoproteins. LPL is produced mainly in adipose tissue, skeletal and heart muscle, as well as in macrophage and other tissues. After synthesized, it is secreted and translocated to the vascular lumen. LPL expression and activity are regulated by a variety of factors, such as transcription factors, interactive proteins and nutritional state through complicated mechanisms. LPL with different distributions may exert distinct functions and have diverse roles in human health and disease with close association with atherosclerosis. It may pose a pro-atherogenic or an anti-atherogenic effect depending on its locations. In this review, we will discuss its gene, protein, synthesis, transportation and biological functions, and then focus on its regulation and relationship with atherosclerosis and potential underlying mechanisms. The goal of this review is to provide basic information and novel insight for further studies and therapeutic targets. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: LPL Lipoprotein Lipid Triglyceride Inflammation Atherosclerosis

Abbreviations: LPL, lipoprotein lipase; TG, triglyceride; CM, chylomicron; VLDL, very low density lipoprotein; FFA, free fatty acid; FA, fatty acid; ER, endoplasmic reticulum; LMF1, lipase maturation factor 1; SorLA, sortilin-related receptor with Atype repeats; TGN, trans Golgi network; LS, lysosome; HSPG, heparan sulfate proteoglycans; HS, heparan sulfate; EC, endothelial cell; VEC, vascular endothelial cell; VLDLR, very low density lipoprotein receptor; GPIHBP1, glycosylphosphatidylinositol-anchored high density lipoproteinebinding protein 1; PPRE, peroxisome proliferator activated receptor responsive element; AP-1, anterior protein-1; PPAR, peroxisome proliferator activated receptor; RXR, retinoic acid receptor; LXR, liver X receptor; TNF, tumor necrosis factor; INF-g, interferon-g; PKA, protein kinase A; CRP, C-reactive protein; apoA-V, apolipoprotein A-V; apoE, apolipoprotein E; apoC, apolipoprotein C; CREB-H, cAMPeresponsive elementebinding protein H; Angptls, angiopoietin-like proteins; AS, atherosclerosis; TRL, triglyceride-rich lipoproteins; RLP, remnant-like lipoprotein particle; LDL, low density lipoprotein; ox-LDL, oxidized low-density lipoprotein; IL-6, interleukin-6; Ox-PLs, oxidized phospholipids; LDLR, LDL receptor; LRP, LDL-receptor associated protein. * Corresponding authors. E-mail addresses: [email protected] (W.-D. Yin), [email protected] (C.-K. Tang). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.atherosclerosis.2014.10.016 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.

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Contents 1. 2. 3. 4. 5.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Gene and structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Synthesis and transportation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Biological functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 5.1. Transcriptional regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 5.2. Post-transcriptional regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 5.3. Regulation by interactive proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.3.1. Apolipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.3.2. cAMPeresponsive elementebinding protein H (CREB-H) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.3.3. The angiopoietin-like proteins (Angptls) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.3.4. ATPebinding cassette G1 (ABCG1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 5.4. Hormonal regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Role in AS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.1. LPL enhance the adhesion of monocytes to the endothelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.2. The catalytic action of LPL results in the formation of atherogenic lipolytic products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 6.2.1. Lipolytic products act on VECs to promote the entry of lipoproteins into arterial intima . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 6.2.2. The pro-atherogenic effect of FAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 6.2.3. The pro-atherogenic effect of RLPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 6.3. LPL promotes the retention of RLPs in the arterial intima . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 6.4. LPL acts as a structural cofactor facilitating the cellular uptake of lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

1. Introduction Lipoprotein lipase (LPL) is a central enzyme in overall lipid transport and metabolism, and plays a crucial role in human lipid homeostasis and energy balance. It is mainly synthesized by parenchymal cells in adipose, skeletal and cardiac muscle. The physiological function of LPL is to catalyze the hydrolysis of triglycerides (TG) in plasma TG-rich lipoproteins, chylomicrons (CM) and very low density lipoproteins (VLDL) at the capillary endothelial cell (EC) surface, providing free fatty acids (FFAs) and glycerol for tissue utilization [1e3]. However, LPL is also present in the vessel wall due to its expression in macrophages and smooth muscle cells (SMCs). In this case, LPL likely contributes to the lipid accumulation in these cells [4]. After release of FFAs, the resulting triglyceride-poor and cholesterol-enriched lipoprotein remnant particles in association with LPL are meant to be cleared by the liver. Redundant lipolytic products (FFAs, lipoprotein remnants) induce a series of actions implicated in atherosclerosis (AS), such as inflammation and lipid accumulation [5]. LPL expression and activity can be regulated at multiple levels in a tissue-specific manner in response to energy requirement. LPL is closely related to metabolic disorders, such as obesity, diabetes and hypertriglyceridemia [6]. Because of its tissue-specific activity, LPL also directly and/or indirectly participates in the pathogenesis of AS [7]. 2. Gene and structure The gene of LPL is located on chromosome 8p22, spans 30 kb and is divided into 10 exons. It is a member of the TG lipase gene family, which also includes hepatic lipase, pancreatic lipase and endothelial lipase. The complementary DNA for human LPL shows that the gene encodes 448 amino acids with a 27-amino-acid signal peptide. The first exon encodes the 50 untranslated region and the signal peptide plus the first two amino acids of the mature protein. The next eight exons encode the remaining 446 amino acids, and

the 10th exon encodes the long 30 untranslated region of 1948 nucleotides that also contains some translational regulatory elements [8e10]. LPL, a 55-kDa glycoprotein, is organized into two structurally-distinct domains, an N-terminal domain and a smaller C-terminal domain with a flexible peptide connecting the two domains [11]. The N-terminal domain contains a lipid-binding site, a heparin-binding site, an apolipoprotein C-II (apoC-II) interaction site, a catalytic triad (Ser132, Asp156, and His241) responsible for lipolysis, and a 22-amino acid loop covering the catalytic site essential for interaction with lipid substrates [12]. The C-terminal domain contains a heparin-binding region important for binding lipoproteins. Native LPL monomers are arranged in a head-to-tail orientation to form a noncovalent active homodimer [13,14]. The C-terminal domain of monomer LPL is positioned in close proximity to the active-site region on the other subunit. Lipid substrates are envisioned to interact with LPL via the C-terminal domain for presentation to the catalytic cleft [11]. Dissociation of the LPL dimer into monomers leads to an irreversible loss of the catalytic function [15] (Fig. 1). 3. Synthesis and transportation LPL is primarily synthesized in the parenchymal cells of heart, skeletal muscle and adipose tissues, and then transported to the luminal surface of vascular endothelial cells (VECs) to exert its main physiological function to hydrolyze plasma lipoproteins. LPL is first synthesized as an inactive and monomeric proenzyme in the rough endoplasmic reticulum (ER), and then glycosylated to achieve its dimeric active form with the presence of lipase maturation factor 1 (LMF1) [16]. LMF1 is an ER membrane protein involved in the posttranslational folding, assembly and stabilization of active LPL homodimer [17]. Without LMF1 in the ER, LPL homodimers are rapidly dissociated to misfolded monomers which are prone to aggregation [18]. There is an intracellular pool of inactive LPL containing aggregated misfolded LPL, which is destined for ER


Fig. 1. Lipoprotein lipase model. Functional lipoprotein lipase is arranged in a head-totail dimer. The N-terminal domain contains the active-site residues, apoC-II interaction site, and the lid that covers the catalytic cleft. The C-terminal domain that contains a heparin-binding region and elements required for lipolysis is positioned in close proximity to the active-site region on the other subunit. Lipid substrates are envisioned to interact via the C-terminal domain for presentation to the catalytic cleft.

degradation [19,20]. The active LPL is then delivered to the Golgi for further modification, sorting and packaging. After passing through the Golgi, a part of active LPL can bind to sortilin-related receptor with A-type repeats (SorLA) in the trans Golgi network (TGN) and is sorted to late endosomes (LEs), where SorLA returns to the TGN and LPL is delivered to lysosomes (LS) for degradation [21]. Thus, some newly-synthesized LPLs are degraded prior to being secreted. The rest active LPL, after being secreted, binds to heparan sulfate proteoglycans (HSPG) on parenchymal cell surface through either constitutive and/or regulated mechanisms [22]. Majority of LPLexpressing cells spontaneously release LPL through the constitutive mechanism. On the other hand, the regulated release, which is aimed at the enzyme packaging and assembly in secretory vesicles, occurs in response to secretagogues, such as heparin [23]. Secreted LPL can also be up-taken through sortilin and LDL receptor, followed by being delivered to lysosomes for degradation. Cell surface-bound LPL also undergoes degradation after being internalized, depending on the number of HSPG binding sites and the extent of HSPG sulfation [24]. HSPGs on parenchymal cell surface serve as a temporary docking site and an auxiliary reservoir of LPL. HSPGs are proteoglycans bearing heparan sulfate (HS) side chains attached to specific serine residues of a core protein. They can attach to the cell surface through a glycosyl-phosphatidyl inositol anchor in case of glypican or traverse the cell membrane with the syndecan family. The HS side chains are polymers of repeating disaccharides that can interact with multiple ligands, including LPL [25,26]. To hydrolyze circulating lipoproteins, the secreted LPL that is sequestered on the parenchymal surface through binding to HSPGs is needed to translocate from parenchymal cells to the vascular lumen. First, the parenchymal surface HSPGs are cleaved to release the sequestered LPL. Heparanase secreted from ECs is known to cleave HSPGs to release heparan sulphate oligosaccharides [27]. It contains a latent 65-kDa form and an active 50-kDa form. Active heparanase releases LPL from the myocyte surface, and latent heparanase stimulates movement of intracellular LPL to replenish the released reservoir via HSPG-mediated RhoA activation [28]. With the cleavage of parenchymal cell surface-bound HSPGs, LPL binds to oligosaccharides non-covalently, likely preventing LPL degradation in interstitial fluid and serving as extracellular chaperones to enable transport of LPL to ECs [29]. Subendothelial extracellular matrix consisting of collagens, fibronectin, laminin and glycosaminoglycans, such as HSPG, is able to bind, sequesters and stabilizes the secreted LPL [30,31]. Thereafter, LPL is

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translocated from the basolateral to the apical side of VEC via a transcytosis process: binding to HSPGs, internalized and then transferred by VLDL receptor (VLDLr) from the interstitial space to the vascular lumen [32]. Finally, LPL binds to luminal surface of ECs through HSPG. Luminal LPL can also be internalized into an endothelial endocytic compartment, which favors HSPGeLPL binding. This process facilitates the recycling of internalized LPL complex back into the subendothelial space or insertion onto the cell surface, thereby allowing ECs to maintain an auxiliary pool of the enzyme [33,34]. Recently, glycosylphosphatidylinositol-anchored high density lipoproteinebinding protein 1 (GPIHBP1), a GPI-anchored protein of capillary ECs, has also been shown to bind to LPL readily in the subendothelial space and transport it to the capillary lumen, thereby serving as a binding site for LPL in the capillary lumen and creating “a platform for lipolysis” [35]. Mature GPIHBP1 contains a negatively charged acidic domain, which can potentially bind to the positively charged domain of apolipoproteins in lipoproteins and the positively charged heparin-binding domain in LPL. GPIHBP1 has a much higher affinity for LPL than for other molecules in the subendothelial space including HSPG. Thus, GPIHBP1's acidic domain may first function as a lasso to bind LPL's heparin-binding domains and pull LPL away from HSPGs in the interstitium, and then act as a transporter to facilitate the translocation of LPL to the lumen. GPIHBP1 moves bidirectionally across ECs continuously to help LPL traverse ECs in transcytotic vesicles, and then insert onto the luminal cell surface or “hand off” LPL to another anchor protein (GPIHBP1, HSPG) on the capillary wall where LPL-mediated lipolysis of circulating lipoproteins occurs [36]. However, the recent research showed that GIHBP1-/- mice are hypertriglycemic, but Syndecan/ mice have only slightly elevated plasma TG level, suggesting that GPIHBP1 plays a much more important role in lipolysis of plasma lipoproteins [37,38]. HSPG is widely distributed on the surface of VEC, parenchymal and macrophage cell as well as in the arterial wall to serve as a binding site for LPL. In addition to facilitating lipolysis on capillary endothelial surface, HSPG then also acts as an LPL reserve and a key factor in arterial intima lipid deposition which is a major risk factor for AS. On the other hand, GPIHBP1, which is exclusively expressed in capillaries but not in larger blood vessels, is responsible for the translocation and binding of LPL to the luminal surface of capillaries leading to a platform for lipolysis. Recently, GPIHBP1 has been found to promote triglyceride-rich lipoprotein margination in capillaries [39]. Taken together, evidence suggest that GPIHBP1 is the platform for lipolysis (Fig. 2). 4. Biological functions The main biological function of LPL is to catalyze the hydrolysis of triglycerides in plasma lipoproteins at the luminal surface of capillaries, thereby producing FFAs and glycerol for tissue utilization and remnant particles for clearance [5]. Although LPL is primarily synthesized by the parenchymal cells of heart, skeletal muscle, and adipose tissues, it is also expressed in many other cells and tissues, such as macrophages, the nervous system, the liver, the proximal tubules of the kidneys, adrenals, pancreatic islet cells, and the lungs [40]. LPL expressed in different tissues exerts differential physiological functions. Heart and skeletal LPL is mainly responsible for catalyzing the lipolysis of plasma lipoproteins, reducing plasma triglycerides and providing substrate (FFA) for oxidization to produce energy [33,41]. In adipose tissue, FFAs provided by LPLmediated hydrolysis of plasma TG-rich lipoproteins are preferentially used for lipid storage, suggesting a role for LPL in initiation and development of obesity [42]. LPL is also a marker for adipocyte differentiation, since LPL expression is increased in parallel with

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Fig. 2. LPL synthesis, secretion and translocation. Following synthesis in the ER, LPL is exported to the Golgi for either secretion or lysosomal degradation. After secretion, LPL binds to cell surface HSPG, and translocates to the abluminal side of the EC. Subsequently, the enzyme is transcytosed to the apical surface where it facilitates lipoprotein hydrolysis.

cellular TG accumulation during the differentiation process of preadipocytes [43]. LPL is only transiently expressed in the scattered Kupffer cells of embryonic liver. However, the liver can also take up the circulating LPL from the blood in adulthood [44,45]. Over-expression of LPL in the liver results in a significant increase of TG levels, impairment of insulin sensitivity and its downstream signaling pathway, and inhibition of endogenous glucose production, leading to lipid accumulation, lipotoxicity and insulin resistance [46]. LPL is present throughout the nervous system, including the brain, spinal cord, and peripheral nerve. It is expressed in dentate granule cells, pyramidal cells of cortex, Purkinje cells of cerebellum, CA1eCA4 cells of hippocampus, and the endothelial surfaces throughout the brain [47]. LPL appears to serve as a transport protein for cholesterol and vitamin E to neurons, which may help the survival, plasticity, and regeneration process of neuronal system. LPL is also essential for VLDL-stimulated differentiation of Neuro-2A cells, suggesting a potential role for LPL in the recycling and scavenging of lipids released from degenerating nerve [48]. In addition, LPL is highly expressed in the lactating mammary gland, which is likely derived from delipidated adipocytes rather than from mammary epithelium, and promotes milk fat accumulation [49].

5. Regulation LPL expression can be regulated at both transcriptional and posttranscriptional levels. Some proteins that interact with LPL have also been shown to participate in the tissue-specific regulation of LPL [50]. Nutrient states and hormonal levels all have divergent influence on the regulation of LPL. They can modify the regulation of LPL directly or indirectly via affecting the regulatory roles of LPL interacting proteins [51,52]. Thus, LPL is regulated through complex mechanisms at multiple levels in response to energy requirements and hormone changes so as to maintain lipid homeostasis [1,6].

5.1. Transcriptional regulation The 50 regulatory region of LPL gene extends ~4 kb from the transcription start site, and contains a large number of specific cisacting elements, including CT element, sterol regulatory element 2, interferon-g responsive element, the peroxisome proliferator activated receptor responsive element (PPRE), the oxysterol liver X receptor responsive element, the nuclear factor-1-like motif, anterior protein-1 (AP-1) element, and AP-1-like element [6,53]. Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors and have three main isoforms: PPAR a, b and g. They can regulate the expression of certain genes implicated in lipid metabolism through binding to the PPRE site of the genes. PPARs and retinoic acid receptor (RXR) can form a PPAR-RXR heterodimer so as to bind to the PPRE in the LPL promoter and up-regulates the expression of LPL in a tissuespecific manner [54]. PPARg predominantly influences adipocyte differentiation and lipid storage [55,56]. PPARa and PPARd are closely associated with lipid accumulation in hepatocytes and macrophages [57]. PPARs can be activated by a multitude of chemical compounds, such as fatty acids (FAs) and especially LPL lipolytic products. Thus, a positive regulatory feedback loop involving FA, PPARs and LPL seems to exist to promote plasma TG clearance and lipid storage [58,59]. RXR and Liver X receptor (LXR) also regulate LPL expression in a tissue-specific manner. RXR can up-regulate LPL expression in plasma, heart and skeletal muscle, but not in adipose tissue [60]. On the other hand, LXR promotes the expression of LPL in the liver and macrophages, but has little effect in adipose tissue, heart and skeletal muscle [61]. In addition, tumor necrosis factor (TNF) and interferon-g (INF-g) can inhibit LPL gene transcription by blocking the nuclear factor Y-CCAAT interaction via casein kinase 2 and PI3-K/Akt signaling pathways, respectively [62,63]. Furthermore, transforming growth factor-b (TGF-b) enhances, while protein kinase A (PKA) inhibits, the transcription of LPL via TGF responsive element and cAMP element, respectively [64,65].


5.2. Post-transcriptional regulation Epinephrine inhibits LPL expression via interacting with 30 UTR of LPL mRNA [66]. Protein kinase Ca (PKCa) depletion results in the formation of an RNA-binding complex that inhibits LPL translation through binding to the 30 UTR of LPL [64]. Calcium can regulate LPL expression at the posttranslational level by triggering its folding into the active form [67]. Both glucocorticoids and insulin are essential for LPL translation and transmembrane transport [68]. Creactive protein (CRP) also increases macrophage LPL expression and secretion at the posttranscriptional level [69]. MicroRNAs (miRNAs), another important mechanism for posttranscriptional regulation of LPL, are small RNAs that can inhibit gene expression via base-pairing with the 30 UTR of target mRNA [70]. To date, several miRNAs are found to play a role in lipid metabolism and AS, such as miR-27, miR-29, miR-33, miR-46, miR378 and miR-467 [71,72]. In dendritic cells, miR-29a can inhibit LPL expression by targeting 30 UTR of LPL mRNA [73]. Ahn et al. have found that miR-467b can also repress hepatic LPL activity, while it is unclear if inhibitory effect of miR-29a and miR-467b is synergetic, competitive or irrelevant [74]. Recently, our team has been working on the regulatory effects of microRNAs, specifically miR-467b and miR-27a/b on LPL. Our studies have shown that miR-467b targets LPL mRNA in RAW 264.7 macrophages and attenuates lipid accumulation and proinflammatory cytokine secretion, and that, miR476b over-expression protects apoE/ mice from AS by reducing lipid accumulation and inflammatory cytokine secretion in vivo [75,76]. The miR-27a/b regulate the expression of LPL gene in THP-1 macrophages through binding to its 30 UTR, and may play a key role in cholesterol influx and progression of AS [77]. Different miRNA families can share mRNA targets, and a short binding distance between miRNAs may strengthen the repressive effect of multiple miRNAs on one target. MiR-27 and miR-29 are shown to act in a combinatorial manner to enhance the repressive effect on LPL expression. Meanwhile, miR-27 is also shown to inhibit the translation of PPARg, the key transcriptional regulator of LPL. Therefore, these miRNAs, transcription factors together with LPL mRNA may form a feed-forward loop to enhance the repressive effect on LPL expression [78]. 5.3. Regulation by interactive proteins 5.3.1. Apolipoproteins Apolipoproteins are an essential component of lipoproteins, which can emulsify the lipid molecules, and transport lipids in a water-based circulation (blood, lymph). They have both structural and metabolic functions. For example, apolipoprotein A-I (apoA-I), a major component of high density lipoprotein (HDL), is important for reverse cholesterol transport [79]. However, apolipoprotein A-V (apoA-V) is inversely correlated with plasma TG. ApoA-V/ mice display severe hypertriglyceridemia [80,81]. Like LPL, apoA-V can also bind to vascular cell surface HSPG, thus promoting lipoprotein interaction with LPL and facilitating LPL-catalyzed TG lipolysis in these lipoproteins [82]. However, a recent study showed a positive correlation between apoA-V and TG levels [83]. In hypertriglyceridemia, apoA-V may be up-regulated as the consequence of high levels of TG, but the TG-lowering effect of apoA-V is not sufficient to normalize TG levels. Interestingly, apoA-V also binds to GPIHBP1, the major binding site for luminal LPL and the platform for lipolysis [84,85]. Thus, apoA-V promotes LPL-mediated lipolysis through enhancing attachment of lipoproteins to EC surface HSPG and/or GPIHBP1. Apolipoprotein B (ApoB) and apolipoprotein E (apoE) are the ligands for cell-surface receptors, which target lipoproteins to specific tissues for uptake through receptor-mediated endocytosis.

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However, apoE is shown to effectively inhibit LPL-mediated lipolysis of VLDL and CM both in vitro and in vivo [86,87]. ApoC-II, contained in HDL, VLDL and CM, plays an important role in plasma lipid metabolism through acting on LPL. It functions as a cofactor for the enzyme to fully activate the catalytic function of LPL [88,89]. It also enhances the affinity of LPL for lipoprotein particles via forming an apoC-II-LPL complex so as to facilitate LPL's catalyze function [90]. In contrast, apoC-I and apoC-III have been shown to inhibit LPL activity in vitro. Overexpression of apoC-I/III in mice leads to hypertriglyceridemia [91,92]. A null-mutation in apoCIII as shown in the Lancaster Amish leads to low plasma apoCIII levels and confers a favorable lipid profile with low plasma TG levels, resulting in cardioprotection [93]. A recent study showed that apoC-I and apoC-III inhibit lipolysis by displacing LPL from lipoprotein particles, and promote the irreversible inactivation of LPL by angiopoietin-like protein 4 (angptl4) [90]. Apolipoprotein D (ApoD), unlike canonical apolipoproteins that are mainly produced in the liver, is an atypical apolipoprotein with a broad tissue distribution. It has been shown that apoD promotes LPL-mediated hydrolysis of VLDL in vitro, consistent with its TG-lowering action in vivo [94]. 5.3.2. cAMPeresponsive elementebinding protein H (CREB-H) CREB-H, an endoplasmic ERebound transcription factor, is highly and selectively expressed in the liver and small intestine and exhibits an impact on triglyceride metabolism. CREB-Hedeficient mice display severe hypertriglyceridemia. Further studies showed that CREB-H can increase LPL activity by up-regulating the expression of LPL coactivators, apoC-II and apoA-V [95]. As a transcription factor, CREB-H is also structurally related to sterol regulatory element binding protein and PPRE, which also exist in the 50 regulatory region of LPL, indicating that CREB-H may directly regulate LPL activity through these responsive elements [96]. 5.3.3. The angiopoietin-like proteins (Angptls) Angptls are a family of secreted glycoproteins present in both tissues and blood with pleiotropic effects on vascular cells, stem cell biology, and lipid metabolism. Three members (Angptl3, Angptl4 and Angptl8) have effects on lipase activities, plasma lipids and energy metabolism. All family members share a common architecture, comprising two major domains, an N-terminal coiled-coil domain with ability to inactivate LPL, and a C-terminal fibrinogen-like domain. They are prone to be cleaved into functional free domains by proprotein convertases, and the LPL inhibitory effects of N-termini are fully activated after cleavage [97]. Specifically, Angptl3 and Angptl4 inhibit LPL activity and are associated with hypertriglyceridemia [98]. Both of them play a role in LPL-mediated lipid distribution, but differ in their tissue expressions and regulations. Angptl3 is mainly produced by the liver at stable levels and it has been suggested that Angptl3 is involved in the redirection of TGs to adipose tissue during feeding [97,99]. Angptl3 reduces LPL catalytic activity, but does not alter the selfinactivation rate of LPL. In addition, there is a positive correlation between Angptl3 and HDL-cholesterol levels, which may result from Angptl3 inhibition of the effects of endothelial lipase (EL) on HDL phospholipids, since EL hydrolyzes HDL phospholipid and hence decreases plasma HDL levels, angptl3 has been reported to inhibit EL activity [99e102]. Angptl4 mainly plays a role in adipose tissue in fasting state [97]. It effectively inhibits LPL activity by catalytically converting LPL from active dimers into inactive monomers [103,104]. However, recent studies suggest that Angptl4 is a reversible and noncompetitive inhibitor of LPL that could form a complex with LPL but LPL regains its activity after dissociation [105]. Angptl4 tends to form oligomers on the cell surface. Like LPL, Angptl4 can bind to HSPG on

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the cell surfaces where the inactivation of LPL occurs and Angptl4 tends to form oligomers at these sites [106,107]. Binding of LPL to GPIHBP1 prevents LPL from inactivation by Angptl4 [76,107]. It has been suggested that Angptl4 is a fasting-induced regulator of LPL activity in adipose tissue [6]. In fasting, Angptl4 is primarily induced in adipose tissue so as to suppress LPL activity and redirect TGs to the heart and skeletal muscle to maintain basic physiological functions [108e110]. Once refeeding, this process is rapidly reversed. LPL activity reaches a relatively high level in adipose tissue for energy storage. In the heart, Angptl4 expression is significantly up-regulated by dietary FAs via PPAR, resulting in inhibition of LPL activity and subsequent prevention of lipid overload and FA-induced toxicity [111e113]. Angptl8, a newly recognized Angpts family member, has been implicated in both TG and glucose metabolism. It is expressed in the liver and adipose tissue, and circulates in plasma. Angptl8 may activate Angptl3 by increasing its N-terminal cleaved form, and act together with Angptl3 to coordinate the trafficking of TGs to tissues in response to food intake [99]. It was reported that Angptl8/ mice showed a significant decrease in TG levels and an increase in LPL activity on feeding, suggesting an important role for ANGPTL8 in lipoprotein metabolism [3]. 5.3.4. ATPebinding cassette G1 (ABCG1) A recent study showed that ABCG1 controls LPL activity and promotes lipid accumulation in human macrophages, suggesting an important role for ABCG1 in the regulation of macrophage LPL [114]. ABCG1 is generally considered as a membrane transporter and plays an important role in reverse cholesterol transport along with ABCA1 [115]. However, it was recently reported that the intracellular ABCG1 regulates the trafficking of cholesterol and secretory pathway [116,117]. Thus, macrophage intracellular ABCG1 may promote LPL secretion and its binding to cell surface HSPG through transporting cholesterol, facilitating the lipoprotein uptake and foam cell formation and contributing to AS. 5.4. Hormonal regulation Hormones also significantly and divergently regulate LPL activity. Insulin has a major effect on LPL activity in adipose tissue, where it up-regulates LPL activity through both transcriptional and posttranscriptional mechanisms [118]. Growth hormone and sex steroid hormones, such as testosterone and estrogen, inhibit adipose tissue LPL activity and promote lipid mobilization, but increase heart and skeletal muscle LPL activities [52]. Thus, they inhibit lipid storage and facilitate lipid oxidation, beneficial for weight loss. Testosterone reduces femoral and abdominal wall adipose tissues through androgen receptor [119]. Estrogen decreases LPL mRNA as well as TG accumulation in 3T3-L1 adipocytes, likely due to the presence of an AP-1-like TGAATTC sequence in LPL gene [120]. Cold exposure stimulates LPL activity in brown adipose tissue through transcriptional and posttranscriptional mechanisms involving b-adrenergic stimulation [121]. Adipose tissue usually refers to white adipose which functions as a storage organ for excess lipids. However, brown adipose tissue (BAT) contains lots of mitochondria to dissipate energy. Upon cold-induced activation BAT increases its energy demand to produce heat by up-regulating local LPL, and subsequently promotes the uptake of TRLs into BAT. Therefore, LPL in BAT may confer a cardioprotective effect through accelerating plasma TG clearance [122]. Both chronic and acute stresses decrease LPL activity in white adipose tissue through the effects of catecholamines, which decrease LPL activity at the translational level [123]. Thyroid hormone increases LPL activity through negative regulation of LPL inhibitor Angptl3 gene expression [124] (Table 1).

Table 1 Regulation of LPL. LPL expression is regulated at transcriptional and posttranscriptional levels in a tissue-specific manner. Interacting proteins plays an important role in the regulation of LPL activity. Hormonal and nutritional regulation can affect the regulatory roles of interacting proteins or directly modify the regulation of LPL. Finally, the tissue-specific regulation of LPL activity in response to energy requirements and hormonal changes usually involves complex mechanisms at multiple levels. Level

Factor

LPL

Reference

Transcriptional

PPAR, RXR, LXR TNF, INF, PKA FA, Ca, CRP MiR-27, MiR-29, MiR-467 apoA-V, apoC-II, apoD apoE, apoC-I, apoC-III Angptl4, Angptl3, Angptl8 insulin, glucocorticoids, thyroid hormone growth and sex hormone, catecholamine,

[ Y [ Y [ Y Y [

[53,59,60] [61e63] [58,66,68] [72e77] [79,87,93] [85,90,91] [96e106] [67,121,127]

Y

[51,122,126]

Post-transcriptional Interactive protein

Hormone

[andYrepresent directional effect the “factor” on “LPL” activity at different “level”.

6. Role in AS AS is the underlying cause of heart attacks, stroke and other cardiovascular diseases, and poses a serious threat to human health. Lipid metabolism disorder and inflammation are the two main risk factors for the occurrence and development of AS. Recently, AS has been generally viewed as a form of chronic inflammation, which is induced and perturbed by lipid accumulation. AS is triggered by damage of arterial ECs, followed by increased chemokines and adhesion molecules to cause the recruitment and infiltration of monocytes. The monocytes then differentiate into macrophages and transform into lipid-loaded foam cells through the uptake of lipoproteins, characteristic of the fatty streaks, an early lesion of AS, and then advanced atherosclerotic lesions [125,126]. Except for its catalytic effect on lipoproteins, LPL itself and its lipolytic products all play important roles in the development of AS. However, the roles of LPL in the development of AS have been controversial, since both pro-atherogenic and anti-atherogenic effects have been reported. For example, our previous studies suggest that NO-1886 (Ibrolipim), a lipoprotein lipase-promoting activator, improves glucose and lipid metabolism and functions as a suppressor of AS [127e129]. LPL in certain tissues, such as heart, skeletal muscle and adipose tissue, has been viewed as an antiatherogenic enzyme by reducing atherogenic lipoproteins or increasing HDL through its effects on circulating lipoproteins [130]. However, LPL in aorta has been also suggested to have proatherogenic effect [131]. Solely raising plasma LPL without increasing vessel wall LPL results in decreased TG and increased HDL to confer protective effects on AS. However, any increase in vessel wall LPL is associated with increased atherogenesis, suggesting that the roles of LPL in the development of AS depend on its locations [132]. The general consensus is that plasma LPL, which is (that derived predominantly from the adipose tissue and muscle and binds to ECs) exerts an anti-atherogenic effect, while vessel wall LPL (that is mainly derived from macrophages) confers a proatherogenic effect [5,133]. In this review, we have focused on the pro-atherogenic role of LPL in the arterial wall, which promote AS mainly through generating atherogenic lipolytic products and acting as a structural cofactor facilitating cellular lipid uptake. 6.1. LPL enhance the adhesion of monocytes to the endothelium Luminal surface LPL, bound with HSPG or GPIHBP1, not only exerts its physiological function of hydrolyzing TGs in plasma TGrich lipoproteins, but also functions as a monocyte adhesion


protein enhancing the adhesion of monocytes to the endothelium by simultaneously binding to endothelial and monocyte surface HSPG. Moreover, monocyte surface LPL can further promote its adhesion to arterial subendothelial matrix [134,135]. 6.2. The catalytic action of LPL results in the formation of atherogenic lipolytic products With the lipolysis of TGs in TG-rich lipoproteins (TRL), LPL converts the plasma CMs and VLDLs into smaller remnant lipoproteins, FFAs, phospholipids, monoglycerides and diglycerides. These actions may confer a protective effect on the highly atherogenic TG-rich lipoprotein profile. However, the production of high and localized concentrations of FFAs and cholesterol-rich remnant lipoprotein particles also plays an important role in the development of AS. 6.2.1. Lipolytic products act on VECs to promote the entry of lipoproteins into arterial intima It was reported that lipolytic products including FFAs, lipoprotein remnant particles and modified lipoproteins, cause vascular injury and increase endothelial layer permeability [136]. Vascular injury is a principal cause of the initial recruitment of macrophages to the arterial wall, and may serve as a trigger in the development of AS [125]. Increase in the permeability of the arteries to LDL and RLP leads to augmented lipid accumulation in the subendothelial space, resulting in inflammatory events and subsequent foam cell formation [137]. It is well established that oxidized low-density lipoproteins (ox-LDL) plays a role in atherogenesis by inducing EC apoptosis and increasing endothelial permeability [138]. Recently, it has also been revealed that remnant lipoprotein particles impair endothelial function via direct and indirect effects on endothelial nitric oxide synthase (eNOS) and by stimulating secretion of inflammatory factors, such as CRP, IL-6, and TNF-a, from multiple origins [139]. Remnant lipoproteins may accelerate senescence of endothelial progenitor cells through inhibiting telomerase activity via the reactive oxygen species-dependent pathway or altering microRNA levels eventually resulting in endothelial dysfunction and promoting the entry and retention of remnant lipoprotein particles in the vessel wall [140,141]. 6.2.2. The pro-atherogenic effect of FAs FAs resulting from the lipolysis of VLDL by LPL provide the substrates for tissue use. However, the local high levels of FAs trigger a series of events involved in AS, which can be cytotoxic. First, the redundant FAs will induce the expression of cell adhesion molecules and inflammatory cytokines in ECs and the apoptosis of ECs, which may play a role in the initiation of AS [142e144]. Second, FAs, especially saturated FAs, can activate toll-like receptor (TLR)2 and 4, and FA-binding protein 4 (FABP4) in macrophages and then stimulate pro-inflammatory cytokine production and ER stress, leading to acceleration of atherogenesis [145,146]. Third, FAs are shown to increase cholesterol uptake and reduce cholesterol efflux [147], and can also be re-esterified by macrophages, thus promoting cellular lipid accumulation and subsequent foam cell formation [148,149]. It is predicable that FAs can promote LPL expression by activating PPARs. Increased saturated FA (SAT) levels in the arterial wall have been shown to induce the macrophage LPL production and consequent foam cell formation and AS [150]. However, n-3 FAs are shown to decrease macrophage LPL in parallel with reduction of arterial lipid deposition [151]. Dietary replacement of SFA by n-3 FAs effectively ameliorates adverse plasma lipid profiles and reduces aortic macrophages, macrophage-associated LPL and proinflammatory markers [152]. Thus, unlike SFA, n-3 FAs confer an anti-atherogenic effect. The accumulation of excess free cholesterol

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in macrophages will contribute to AS by stimulating TNF-a and IL-6 production, which trigger ER stress and apoptosis [153]. Recently, it has also been suggested that FFA can fuel macrophage phagocytosis to accelerate the progression of AS [154]. Finally, FA can increase proliferation and migration of SMCs and cause proatherogenic changes in the production of proteoglycans [155]. At the same time, it can further induce the synthesis of LPL in monocytes [150]. Except for FAs, the recent studies suggested that phospholipids, especially oxidized phospholipids (Ox-PLs), another kind of lipolytic lipid produced by LPL, play an important role in AS [156]. It has been reported that Ox-PL can interact with ECs, monocyte/macrophages, platelets and SMCs through acting on different receptors to stimulate various signaling pathways underlying AS [157]. High concentration of Ox-PLs can disrupt endothelial integrity and increase endothelial permeability [158]. Ox-PLs can also facilitate macrophage lipid accumulation and foam cell formation by upregulating CD36 expression [159]. They can even be cytotoxic, and induce apoptosis of macrophages [160]. In the sites of lipid oxidation and accumulation, such as atherosclerotic vessels, Ox-PLs exert pro-inflammatory effects, and promote the expression of inflammatory cytokines and inflammatory reactions [161]. Levels of Ox-PLs in plasma are associated with increased risk of coronary artery disease, and closely related to AS. Therefore, they may serve as a biological marker for atherosclerotic disease. 6.2.3. The pro-atherogenic effect of RLPs Remnant lipoproteins, also known as remnant-like lipoprotein particles (RLPs), including chylomicron remnants and VLDL remnants, can be further hydrolyzed into intermediate-density lipoproteins (IDLs) and low density lipoproteins (LDLs). After release of LPL, the formed RLPs are supposed to be transported to the liver for further clearance [162]. However, they can also enter the arterial wall, where they are preferentially retained and then taken up by macrophages. Compared with the nascent TG-rich lipoproteins, TRL remnants are depleted of TG, phospholipid, and apoC, but enriched in cholesterol esters and apoE with a reduced size. Thus they are more likely to diffuse into the blood vessel wall, and retained by HSPG within the arterial intima and taken up by macrophages [163e167]. Therefore, they are more potentially atherogenic. Indeed, RLP cholesterol level has recently considered as an independent risk factor for atherosclerosis and cardiovascular disease [168,169]. 6.3. LPL promotes the retention of RLPs in the arterial intima It has been suggested that the retention of LDL is an initial step in the development of atherosclerotic lesions [170e172]. LPL plays an important role in the retention of LDL and other RLPs including IDL, small VLDL and chylomicron remnants in the arterial intima by acting as a molecular bridge between RLP and proteoglycans in extracellular matrix [131,173,174]. In atherosclerotic lesions, there are two predominant proteoglycans: versican that is present primarily in areas rich in SMCs, and biglycan that is abundant in the extracellular matrix adjacent to the sites of macrophage infiltration. LPL promotes binding of both oxidized and native LDL to versican and biglycan [175]. Retention increases the residence time of LDL in the intimal matrix, allowing the particles to be modified more extensively. Such a modification promotes their uptake into macrophages through scavenger receptors along with other biologically active lipids, such as oxidized phospholipids, oxysterols and ceramide, triggering inflammatory reactions and other atherogenic events [131,148,161]. Thus LPL plays an important role in the accumulation of atherogenic lipoproteins in the arterial subendothelial matrix and promotes further cellular uptake of lipoprotein particles.

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6.4. LPL acts as a structural cofactor facilitating the cellular uptake of lipoproteins In addition to mediating binding of lipoproteins to the proteoglycans in extracellular matrix of the arterial intima, LPL mediates binding of various lipoproteins (native, modified or remnants) to HSPG on cell surface, leading to a significant accumulation of lipoproteins on cell surface [176]. LPL is not only responsible for the accumulation of atherogenic lipoproteins, but also a crucial factor in their uptake by macrophages [177]. Macrophage LPL is the major source of LPL in the arterial wall and likely promotes foam cell formation and AS [178,179]. Macrophages isolated from mice susceptible to AS show a 2e3 folds increase in LPL mass and activity compared with those from mice resistant to AS, inferring a contributive role for macrophage LPL in the progression of AS [180]. Specific blockade of macrophage LPL production by bone marrow transplantation or cre-loxP gene targeting significantly decreases the development of atherosclerotic lesions [181,182]. However, specific expression of macrophage LPL accelerates atherosclerosis [183]. The exact mechanism by which LPL facilitates macrophage lipid uptake and foam cell formation is still unclear, but some possibilities have been proposed. The first is the ligand-receptor pathway. Like apoE, the most important ligand for receptormediated lipoprotein uptake [162,184], LPL in RLP also acts as a ligand for lipoprotein receptors on the macrophage cell surface, such as LDL receptor (LDLR) and LDL-receptor associated protein (LRP), and then enhance the binding of RLP to these receptors and facilitate the uptake of RLP through receptor-mediated endocytosis [185e187]. The second is the HSPG-mediated pathway. LPL can bridge RLP to cell surface HSPG to concentrate lipoproteins in the vicinity of receptors. Then, HSPG by itself can mediate a direct uptake of RLP via HSPG recycling with entire HSPGeLPLelipoprotein complex, which is independent of feedback inhibition by cellular sterol content. Alternatively, HSPG-bound RLPs can be transferred to vicinal receptors for further uptake [187e189]. Moreover, LPL is also involved in selective cholesterol ester uptake, in which cholesterol esters from the lipoprotein core are taken up

by cells without concomitant uptake of whole lipoprotein particles. This process requires cell surface HSPG independent of scavenger receptor BI (SR-BI) [190,191]. SR-B1and CD36 belong to class B scavenger receptor have been identified as ox-LDL receptor responsible for the uptake of modified lipoproteins especially oxLDL. Unlike LDLR, their expression is not affected by cellular cholesterol content, which may lead to massive lipid accumulation and promote foam cell formation and AS [192,193]. Studies have suggested that CD36-mediated lipid uptake will in turn promote its expression, likely forming a positive feedback loop that aggravates the lipid accumulation in macrophages [194e196] (Fig. 3). In addition to macrophages, another important cell type in atherosclerotic lesions is SMCs. LPL has also been shown to promote the proliferation of vascular SMCs. Such cells are known to secrete extracellular matrix proteins that promote the formation of fibrous plaques, a prominent characteristic of the later stages of atherogenesis [197]. 7. Conclusions and perspectives Overall, LPL is a fascinating enzyme playing an important role in lipid metabolism, energy balance and other related biological functions as well as in the diseases associated with AS. It is an important multifunctional enzyme produced by many tissues. Although the predominant function of LPL is to hydrolyze the TG core of circulating TG-rich lipoproteins, it is also implicated in the uptake of lipoprotein. Therefore, LPL may confer both pro- and antiatherogenic effects, depending on its locations and sources. Briefly, the enzyme expressed in the adipose tissue and muscle and secreted into blood is generally regarded as anti-atherogenic through its anti-dyslipidemic actions, whereas the arterial pool of LPL produced by macrophages and SMCs is considered to be proatherogenic by enhancing lipid accumulation and inducing inflammation. Thus, more accurate and precise mechanism still needs further investigation. A better understanding of the regulation of LPL expression should also be put on the agenda. Therefore, it is critical to develop strategies that could be used to modulate its

Fig. 3. Pro-atherogenic role of LPL. With the lipolysis of TRL by LPL, the released FFAs and RLPs may trigger inflammatory response, increase the arterial permeability and induce EC apoptosis. After entering into the arterial wall, RLPs can bind to proteoglycans and cell HSPG, promoting their retention. In the plaques, LPL produced by macrophages and SMCs can further hydrolyze RLPs and facilitate their uptake, leading to lipid accumulation and foam cell formation. Taken together, they promote the development of AS.


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Lipoprotein lipase and atherosclerosis.

Lipoprotein and hepatic lipase gene variants in coronary atherosclerosis.

Lipoprotein lipase deficiency resulting from a nonsense mutation in exon 3 of the lipoprotein lipase gene.

Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.

Lipoprotein lipase.

Lipoprotein lipase.

Lipoprotein lipase.

Lipoprotein lipase: recent contributions from molecular biology.

Lipoprotein lipase gene sequencing and plasma lipid profile.

Structure and polymorphic map of human lipoprotein lipase gene.

Rat heart lipoprotein lipase.

MicroRNA-590 Inhibits Lipoprotein Lipase Expression and Prevents Atherosclerosis in apoE Knockout Mice.

Purification and characterization of lipoprotein lipase from rat brown fat.

Antibodies to lipoprotein lipase. Application to perfused heart.

Purification and characterization of lipoprotein lipase from pig myocardium.

Release of lipoprotein lipase from fat cells in vitro.

Physiological regulation of lipoprotein lipase.

Activity of lipoprotein lipase in adipose tissues from steers.

Activation of highly purified lipoprotein lipase from bovine milk.

The lipoprotein lipase (clearing-factor lipase) activity of cells isolated from rat cardiac muscle.

Properties of salt-resistant lipase and lipoprotein lipase purified from human post-heparin plasma.

Lipoprotein lipase and hepatic lipase activities are differentially regulated in isolated hepatocytes from neonatal rats.

Purification of salt resistant lipase and lipoprotein lipase from human post-heparin plasma.

Human postheparin plasma lipoprotein lipase and hepatic triglyceride lipase.