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Introduction HDL Metabolism A continuous publication, open access, peer-reviewed journal ACCESS ONLINE REVIEW Primary genetic disorders affecting high density lipoprotein (HDL) Constantine E Kosmas MD, PhD1, Delia Silverio MD2, Andreas Sourlas3, Frank Garcia MD2, Peter D Montan MD2, Eliscer Guzman MD4 1Division of Cardiology, Department of Medicine, Mount Sinai Hospital, New York, NY, USA; 2Cardiology Clinic, Cardiology Unlimited, PC, New York, NY, USA; 3School of Medicine, University of Crete, Heraklion, Greece; 4Division of Cardiology, Department of Medicine, Montefiore Medical Center, Bronx, NY, USA Abstract atherosclerotic disease. This review aims to describe certain There is extensive evidence demonstrating that there is a clear genetic disorders associated with either low or high plasma inverse correlation between plasma high density lipoprotein HDL-C and discuss their clinical features, associated risk for cholesterol (HDL-C) concentration and cardiovascular cardiovascular events, and treatment options. disease (CVD). On the other hand, there is also extensive Keywords: apolipoprotein A-I (ApoA-I), cardiovascular disease evidence that HDL functionality plays a very important role (CVD), genetic disorders, high density lipoprotein (HDL). in atheroprotection. Thus, genetic disorders altering certain enzymes, lipid transfer proteins, or specific receptors crucial for Citation the metabolism and adequate function of HDL, may positively Kosmas CE, Silverio D, Sourlas A, Garcia F, Montan PD, Guzman E. or negatively affect the HDL-C levels and/or HDL functionality Primary genetic disorders affecting high density lipoprotein (HDL). and subsequently either provide protection or predispose to Drugs in Context 2018; 7: 212546. DOI: 10.7573/dic.212546 Introduction describe certain genetic disorders associated with either low or high plasma HDL-C concentration and we will discuss their There is extensive evidence demonstrating that there is a clear clinical features, associated risk for cardiovascular events, and inverse correlation between plasma high density lipoprotein treatment options. cholesterol (HDL-C) concentration and cardiovascular disease (CVD). HDL-C levels are considered a strong predictor for CVD HDL metabolism independently to low density lipoprotein cholesterol (LDL-C) levels.1 Furthermore, studies have indicated that there is a 2–3% HDL is synthesized in the liver and small intestine and is the decrease in the risk for CVD for each 1 mg/dL increase in HDL-C lipoprotein with the highest protein content (approximately levels.2 There is also extensive evidence that HDL functionality 50% of total weight of the particle). When secreted, HDL plays a very important role in atheroprotection.3 contains only a small amount of cholesterol and no cholesteryl esters. HDL is formed by different apolipoproteins, the most The antiatherogenic effects of HDL are mainly attributed to important of which are the apolipoprotein A-I (ApoA-I), which its role in reverse cholesterol transport (RCT) pathway by is secreted predominantly by the liver and intestine as lipid-free promoting the efflux of cholesterol from macrophages in ApoA-I and constitutes approximately 70% of HDL protein, and the arterial wall, thus preventing foam cell formation, and the apolipoprotein A-II (ApoA-II), which is only synthesized by therefore, the initial stages of atherogenesis.4 the liver and constitutes around 20% of the HDL protein. Both Hence, genetic disorders altering certain enzymes, lipid transfer apolipoproteins are required for the normal HDL biosynthesis. proteins, or specific receptors crucial for the metabolism and The newly secreted ApoA-I must acquire lipids in the form of adequate function of HDL, may positively or negatively affect the cholesterol or phospholipids (found in the peripheral cells) in HDL-C levels and/or HDL functionality and subsequently either order to generate the pre-β-HDL. This pathway is mediated by provide protection or predispose to atherosclerotic disease. the action of the ATP binding cassette transporter A1 (ABCA1), In this review, after providing a brief summary of HDL which promotes the transfer of lipids to ApoA-I, resulting in metabolism and its cardioprotective properties, we will lipid-poor ApoA-I.5,6 Kosmas CE, Silverio D, Sourlas A, Garcia F, Montan PD, Guzman E. Drugs in Context 2018; 7: 212546. DOI: 10.7573/dic.212546 1 of 11 ISSN: 1740-4398 REVIEW – Primary genetic disorders affecting high density lipoprotein drugsincontext.com Figure 1. Metabolism of HDL. HDL metabolism Apo A-I Bile for excretion Cholesterol and ABCA1 phospholipids Pre-β-HDL from peripheral cells LCAT Steroid HDL hormones CE SR-B1 synthesis in adrenal cells VLDL/LDL HDL TG CE CETP VLDL/LDL HDL CE TG ABCA1, ATP-binding cassette transporter A1; ApoA-I, apolipoprotein A-I; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; LCAT, lecithin:cholesterol acyl-transferase; LDL, low-density lipoprotein; SR-BI, scavenger receptor class B type I; TG, triglyceride; VLDL, very-low-density lipoprotein. Once pre-β-HDL is in the circulation, lecithin:cholesterol from apolipoprotein B (ApoB)-containing lipoproteins, such as acyltransferase (LCAT), using ApoA-I as cofactor, promotes the very low density lipoprotein (VLDL) and LDL, in exchange the conversion of lecithin into lysolecithin and cholesterol for cholesteryl esters from HDL, thus leading to cholesteryl into cholesteryl esters (CE). CE is a more hydrophobic form of ester depletion and TG enrichment of HDL. Because TGs are not cholesterol, which is then sequestered into the core of the HDL stable in HDL-C, it is degraded by lipoprotein lipase, leading to particle, resulting in the formation of the mature, spherical, an overall net reduction in the size of the HDL particles.10 α-migrating HDL (α-HDL).7 A schematic of HDL metabolism and the genes involved is Finally, scavenger receptor class B type I (SR-BI) promotes the shown in Figure 1. cholesterol uptake from mature HDL by the liver for secretion into the bile, or by the adrenal cells for the synthesis of steroid hormones, in a process that does not involve degradation of Clinical significance of HDL HDL apolipoproteins and is known as selective uptake.8,9 While the main cardioprotective property of HDL relates to HDL-C can be alternatively metabolized and eventually its ability to promote efflux of cholesterol from macrophages transported by the liver, via the action of the cholesteryl ester in the artery wall, a process known as reverse cholesterol transfer protein (CETP). This protein transfers triglycerides (TGs) transport (RCT), HDL may also prevent and/or inhibit Kosmas CE, Silverio D, Sourlas A, Garcia F, Montan PD, Guzman E. Drugs in Context 2018; 7: 212546. DOI: 10.7573/dic.212546 2 of 11 ISSN: 1740-4398 REVIEW – Primary genetic disorders affecting high density lipoprotein drugsincontext.com the development of atherosclerosis via several other The selective upregulation of ApoA-I results in ApoA-I cardioprotective mechanisms. overproduction. It is characterized by elevated HDL-C and ApoA-I levels and has been linked to a reduced risk of CVD.21 HDL has anti-inflammatory effects11 and there is extensive evidence that inflammation plays an important role in the initiation and progression of CVD.12 Furthermore, HDL has ApoC-III variants antioxidant, anticoagulant, and antiaggregating effects; it promotes angiogenesis and enhances endothelial function ApoC-III is a small apolipoprotein, which is synthesized mainly and repair.4 in the liver, is carried in the circulation by VLDL and HDL, and regulates plasma TG homeostasis. This apolipoprotein In addition, HDL may also have beneficial effects on glucose impairs the hydrolysis of triglyceride-rich lipoproteins (TRL) metabolism, as there is evidence that both HDL and ApoA-I by inhibiting the activity of the lipoprotein lipase (LPL) and increase glucose uptake in human skeletal muscle cells, leading delaying the hepatic uptake of TRL by remnant receptors, to reduced plasma glucose levels in diabetic patients.13 thus resulting in elevated plasma TG levels.22,23 Beyond its role on TG metabolism, ApoC-III has been also Conditions that cause high associated with increased risk of CVD. It promotes HDL dysfunction, facilitates the interaction of monocytes and HDL-C levels endothelial cells, stimulates smooth muscle cell proliferation, 24 Genetic conditions associated with elevated HDL-C and alters platelet activity, thus promoting atherosclerosis. levels, are also described as primary familial or secondary Furthermore, plasma ApoC-III concentration is directly related hyperalphalipoproteinemia (HALP) due to the elevated Apo-AI with the plasma TG concentration. Therefore, mutations that and Apo-AII levels observed in these conditions. interrupt ApoC-III function or loss-of-function ApoC-III mutations Patients with HALP tend to be asymptomatic, aside from some are associated with very low plasma TG levels and elevated 25 rare reported cases of juvenile or premature corneal opacities14 HDL-C levels, resulting in a reduction of the risk for CVD. or multiple symmetric lipomatosis,15 and are characterized by Studies have described that carriers of ApoC-III loss-of-function high levels of HDL-C and low incidence of CVD.16 mutations have up to 39% lower plasma TG levels, 22% higher Due to its lack of clinical symptoms, patients are usually plasma HDL-C levels, and 16% lower plasma LDL-C levels. Of identified through the routine assessment of a lipid profile or note, carriers of ApoC-III
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