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(ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia

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(ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia International Journal of Molecular Sciences Review Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia Pei-Yi Chen 1,2,† , Wan-Yun Gao 3,† , Je-Wen Liou 4 , Ching-Yen Lin 2 , Ming-Jiuan Wu 5 and Jui-Hung Yen 2,3,* 1 Center of Medical Genetics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; [email protected] 2 Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970, Taiwan; [email protected] 3 Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan; [email protected] 4 Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 970, Taiwan; [email protected] 5 Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan; [email protected] * Correspondence: [email protected]; Tel.: +886-3-856-5301 (ext. 2683) † These authors contributed equally. Abstract: Dyslipidemia is characterized by increasing plasma levels of low-density lipoprotein- cholesterol (LDL-C), triglycerides (TGs) and TG-rich lipoproteins (TGRLs) and is a major risk factor for the development of atherosclerotic cardiovascular disorders (ASCVDs). It is important to un- derstand the metabolic mechanisms underlying dyslipidemia to develop effective strategies against ASCVDs. Angiopoietin-like 3 (ANGPTL3), a member of the angiopoietin-like protein family ex- clusively synthesized in the liver, has been demonstrated to be a critical regulator of lipoprotein Citation: Chen, P.-Y.; Gao, W.-Y.; metabolism to inhibit lipoprotein lipase (LPL) activity. Genetic, biochemical, and clinical studies Liou, J.-W.; Lin, C.-Y.; Wu, M.-J.; Yen, in animals and humans have shown that loss of function, inactivation, or downregulated expres- J.-H. Angiopoietin-Like Protein 3 sion of ANGPTL3 is associated with an obvious reduction in plasma levels of TGs, LDL-C, and (ANGPTL3) Modulates Lipoprotein high-density lipoprotein-cholesterol (HDL-C), atherosclerotic lesions, and the risk of cardiovascular Metabolism and Dyslipidemia. Int. J. events. Therefore, ANGPTL3 is considered an alternative target for lipid-lowering therapy. Emerging Mol. Sci. 2021, 22, 7310. https:// studies have focused on ANGPTL3 inhibition via antisense oligonucleotides (ASOs) and monoclonal doi.org/10.3390/ijms22147310 antibody-based therapies, which have been carried out in mouse or monkey models and in human clinical studies for the management of dyslipidemia and ASCVDs. This review will summarize Academic Editor: Noemí Rotllan the current literature on the important role of ANGPTL3 in controlling lipoprotein metabolism and Received: 7 June 2021 dyslipidemia, with an emphasis on anti-ANGPTL3 therapies as a potential strategy for the treatment Accepted: 5 July 2021 of dyslipidemia and ASCVDs. Published: 7 July 2021 Keywords: dyslipidemia; TG-rich lipoproteins; ASCVDs; ANGPTL3; lipoprotein lipase Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Dyslipidemia is often characterized by increases in low-density lipoprotein-cholesterol (LDL-C), triglycerides (TGs), and TG-rich lipoproteins (TGRLs) levels in circulation and is associated with obesity, type 2 diabetes, and metabolic syndrome. This condition is a Copyright: © 2021 by the authors. major risk factor for the development of atherosclerotic cardiovascular diseases (ASCVDs) Licensee MDPI, Basel, Switzerland. and myocardial infarction (MI) [1,2]. Although the pharmacological reduction of LDL-C by This article is an open access article statins, ezetimibe, or PCSK9 inhibitors could effectively treat ASCVDs, a notable residual distributed under the terms and risk remains, and these disorders are still the leading cause of death in industrialized conditions of the Creative Commons societies [3–5]. In addition, the efficacy of therapeutic medication for LDL-C-lowering Attribution (CC BY) license (https:// agents is poor in patients with familial hypercholesterolemia-related mutations affecting creativecommons.org/licenses/by/ functional LDL receptors. Therefore, in addition to reducing LDL-C levels, exploring 4.0/). Int. J. Mol. Sci. 2021, 22, 7310. https://doi.org/10.3390/ijms22147310 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 7310 2 of 12 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 12 novel molecular targets of dyslipidemia therapy is ongoing (Figure1). Recently, new going (Figure 1).pharmacological Recently, new approachespharmacological for CVD approaches treatment have for focused CVD ontreatment the regulation have of plasma focused on the regulationTGRLs, which of plasma carry dietary TGRLs, and which synthesized carry dietary TGs, cholesterol, and synthesized and cholesterol TGs, ester in cholesterol, and cholesterolblood vessels ester [1,6 ].in blood vessels [1,6]. FigureFigure 1. The pharmacological1. The pharmacological targets of currenttargets or potentialof current lipid-lowering or potential agents lipid for-lowering dyslipidemia agents therapy. for ACL, ATP-citratedyslipidemia lyase; ANGPTL3, therapy. angiopoietin-like ACL, ATP-citrate protein lyase; 3, Apo(a),ANGPTL3, Apolipoprotein(a); angiopoietin ApoC-III,-like protein Apolipoprotein 3, Apo(a), C-III; ASO, antisenseApolipoprotein(a); oligonucleotides; ApoC CM,-III, chylomicrons;Apolipoprotein HDL, C- high-densityIII; ASO, antisense lipoproteins; oligonucleotide HMG-CoA, 3-hydroxy-3-methyl-s; CM, chylo- glutaryl-coenzymemicrons; HDL, A; HMGCR, high-density 3-hydroxy-3-methyl-glutaryl-coenzyme lipoproteins; HMG-CoA, 3-hydroxy A reductase;-3-methyl IDL, intermediate-density-glutaryl-coenzyme lipoprotein; A; LDL, low-densityHMGCR, 3 lipoproteins;-hydroxy-3-methyl LDLR, low-density-glutaryl-coenzyme lipoprotein A receptor;reductase; LPL, IDL, lipoprotein intermediate lipase;-density Lp(a), lipoproteinlipopro- (a); NPC1L1,tein; Niemann-Pick LDL, low-density C1-like 1lipoproteins protein; PCSK9,; LDLR, proprotein low-density convertase lipoprotein subtilisin/kexin receptor; type LPL, 9; VLDL, lipoprotein very-low-density li- lipoproteins.pase; Lp The(a), approaches lipoprotein for inhibition(a); NPC1L1, of targets Niemann in lipid/lipoprotein-Pick C1-like metabolism1 protein; PCSK9, are highlighted proprotein in the convert- boxes (created with BioRender.comase subtilisin/kexin, accessed type on 29; July VLDL, 2021). very-low-density lipoproteins. The approaches for inhibition of targets in lipid/lipoprotein metabolism are highlighted in the boxes (created with BioRender.com, accessed on 2 July 2021)TGRLs. are envisioned to play essential roles on the progression of ASCVDs [6]. Vari- ants of gene mutations in TGRL metabolism with high TG concentration in plasma exhibits TGRLs are envisionedstrong correlation to play with essential magnitude roles of ASCVD on the risk progression [7]. TGs are presentof ASCVDs in the core[6]. of TGRLs, Variants of gene whichmutati encompassons in TGRL a mixture metabolism of chylomicrons with high and TG very-low-density concentration in lipoprotein plasma (VLDL) particles, and their lipolytic remnants. The TGs could be hydrolyzed to free fatty acids exhibits strong correlation with magnitude of ASCVD risk [7]. TGs are present in the core by lipoprotein lipase (LPL), which is anchored on the luminal surface of capillaries [8]. of TGRLs, which Whenencompass LPL-mediated a mixture TGs of hydrolysis chylomicrons is impeded, and very accumulation-low-density of substrate lipoprotein TGRL particles (VLDL) particles,in and plasma their occurs.lipolytic Regulation remnants. of The LPL TGs activity could represents be hydrolyzed an ideal to strategy free fatty to prevent or acids by lipoproteintreat lipase hypertriglyceridemia (LPL), which is and anchored ASCVDs on [9 the]. Recently, luminal angiopoietin-like surface of capillaries 3 (ANGPTL3), a [8]. When LPL-medmemberiated of TGs the angiopoietin-likehydrolysis is impeded, protein (ANGPTL) accumulation family, isof shownsubstrate to inhibit TGRL LPL activity particles in plasmaand occurs. be involved Regulation in the regulation of LPL of activity lipoprotein represents metabolism. an Thus,ideal ANGPTL3 strategy isto considered prevent or treat ahypertriglyceridemia promising pharmacological and targetASCVDs for treatment[9]. Recently, of dyslipidemia angiopoietin [10,11-like]. In 3 this article, (ANGPTL3), a memberwe review of the currentangiopoietin understanding-like protein of ANGPTL3, (ANGPTL) focusing family, on is its shown role in theto modula- inhibit LPL activitytion and of lipoprotein be involved metabolism, in the regulation dyslipidemia, of lipoprotein and cardiovascular metabolism. events, Thus, and discuss its application as a therapeutic target for the treatment of dyslipidemia and ASCVDs. ANGPTL3 is considered a promising pharmacological target for treatment of dyslipidemia [10,112. Molecular]. In this article, Features we of review ANGPTL3 the current understanding of ANGPTL3, focusing on its role inAngiopoietin-like the modulation proteinsof lipoprotein (ANGPTLs) metabo arelism, a family dyslipidemia, of secreted glycoproteinsand car- com- diovascular events,prising and eightdiscuss members its application (ANGPTL1–8). as a therapeutic ANGPTLs possess target highfor the homology treatment to angiopoietins, of dyslipidemia andwhich ASCVDs. are critical regulators of angiogenesis. However, ANGPTLs could not interact with the angiopoietin receptors Tie1 and Tie2 on the endothelium [12]. Among these ANGPTL 2. Molecular
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