Clin Chem Lab Med 2014; 52(12): 1695–1727 Review Indra Ramasamy* Recent advances in physiological lipoprotein metabolism Abstract: Research into lipoprotein metabolism has devel- summarizes recent advances in knowledge of the molecu- oped because understanding lipoprotein metabolism has lar mechanisms regulating lipoprotein metabolism. important clinical indications. Lipoproteins are risk fac- tors for cardiovascular disease. Recent advances include Keywords: ABCA1; angiopoietin-like proteins; apoC; the identification of factors in the synthesis and secretion apoAI; apolipoprotein E (apoE); cholesterol ester transfer of triglyceride rich lipoproteins, chylomicrons (CM) and protein; chylomicron; LDL receptor; lecithin cholesterol very low density lipoproteins (VLDL). These included the acyl transferase; lipoprotein(a); lipoprotein lipase; micro- identification of microsomal transfer protein, the cotrans- somal transfer protein; propertin convertase subtilisin/ lational targeting of apoproteinB (apoB) for degradation kexin type 9; SR-BI; phospholipid transfer protein; very regulated by the availability of lipids, and the characteri- low density lipoproteins (VLDL). zation of transport vesicles transporting primordial apoB containing particles to the Golgi. The lipase maturation DOI 10.1515/cclm-2013-0358 factor 1, glycosylphosphatidylinositol-anchored high den- Received May 14, 2013; accepted July 8, 2013; previously published sity lipoprotein binding protein 1 and an angiopoietin-like online August 12, 2013 protein play a role in lipoprotein lipase (LPL)-mediated hydrolysis of secreted CMs and VLDL so that the right Abstract 1695 amount of fatty acid is delivered to the right tissue at the Background 1696 right time. Expression of the low density lipoprotein (LDL) Normal lipoprotein metabolism 1697 receptor is regulated at both transcriptional and post- Assembly and secretion of transcriptional level. Proprotein convertase subtilisin/ apoB containing lipoproteins 1697 kexin type 9 (PCSK9) has a pivotal role in the degradation Chylomicrons 1697 of LDL receptor. Plasma remnant lipoproteins bind to spe- Chylomicron assembly 1697 cific receptors in the liver, the LDL receptor, VLDL recep- Apolipoproteins and chylomicron synthesis 1698 tor and LDL receptor-like proteins prior to removal from Catabolism of chylomicrons 1701 the plasma. Reverse cholesterol transport occurs when Lipoprotein lipase and chylomicron metabolism 1701 lipid free apoAI recruits cholesterol and phospholipid to Cellular membrane receptors and chylomicron assemble high density lipoprotein (HDL) particles. The metabolism 1702 discovery of ABC transporters (ABCA1 and ABCG1) and Very low density lipoproteins (VLDL) 1702 scavenger receptor class B type I (SR-BI) provided further VLDL assembly 1702 information on the biogenesis of HDL. In humans HDL- Apolipoproteins and VLDL synthesis 1703 cholesterol can be returned to the liver either by direct Catabolism of VLDL 1704 uptake by SR-BI or through cholesteryl ester transfer pro- LDL receptor and apolipoproteins 1704 tein exchange of cholesteryl ester for triglycerides in apoB Lipoprotein(a) 1707 lipoproteins, followed by hepatic uptake of apoB contain- High density lipoprotein (HDL) 1708 ing particles. Cholesterol content in cells is regulated by Biosynthesis of HDL and reverse several transcription factors, including the liver X receptor cholesterol transport 1708 and sterol regulatory element binding protein. This review ABCA1 and HDL assembly 1708 Apolipoprotein AI and HDL assembly 1709 *Corresponding author: Indra Ramasamy, Department of Blood Cholesteryl ester transfer protein (CETP) Sciences, Worcester Royal Hospital, Charles Hasting Way, Worcester and phospholipid transfer protein 1712 WR5 1EP, UK, E-mail: [email protected] ABCG1 1713 1696 Ramasamy: Lipoprotein metabolism Scavenger receptor BI (SR-BI) 1714 vascular events was reduced by about a fifth. Absolute Other factors in HDL remodeling 1715 reduction in cardiac mortality produced by lowering LDL Hormones and lipid metabolism 1715 cholesterol with statin therapy in a given population Clinical implications of lipoprotein metabolism 1716 depended chiefly on the absolute risk of death due to cor- Future directions 1717 onary exclusion. After adjustments for other risk factors, the risk ratio for upper versus lower tertiles of HDL-choles- terol was similar in participants allocated more intensive as well as those allocated less intensive statin therapy, Background suggesting that the risk reduction was similar in patients with higher HDL concentrations [6]. Cardiovascular disease (CVD) is a major cause of world- Hypertriglyceridemia is a heterogeneous disorder wide mortality. The main clinical entities of CVD are coro- with an unclear association with atherosclerosis and nary artery disease (CAD), ischemic stroke, and peripheral ischemic heart disease. It is difficult to distinguish the arterial disease (PAD). The risk factors for CVD are multi- effects of triglyceride on CVD risk from that of low HDL as factorial and include age, male gender, tobacco smoking, HDL is inversely correlated to triglycerides. Most studies lack of physical activity, dietary habits, blood pressure, that reported an association between fasting plasma tri- and dyslipidemias. glycerides and CVD risk found that after adjustment for The term dyslipidemias, elevated or decreased levels other risk factors (especially HDL) triglyceride was no of lipoproteins, covers a broad spectrum of lipid abnormal- longer an independent risk factor [7]. A meta-analysis of ities. Dyslipidemias may be secondary and related to other studies carried out between 1996 and 2007 reported a pos- diseases or primary and due to the interaction between a itive association between triglyceride levels and stroke [8]. genetic predisposition and environmental factors. Obser- The practice of measuring triglycerides in a fasting condi- vational studies indicated a continuous positive relation- tion to assess a relationship between cardiovascular risk ship between coronary disease risk and blood cholesterol and plasma triglyceride has been questioned as humans concentrations [1]. Further, research from experimental are in post-prandial state for a major part of the day. Mora animals, laboratory investigations, epidemiology, and et al. [9] suggest that HDL-cholesterol, triglycerides, total/ genetic forms of hypercholesterolemia indicate that ele- HDL-cholesterol ratio and apolipoprotein AI (apoAI) are vated total cholesterol and low density lipoprotein (LDL) better predictors of CVD when measured in a non-fast- cholesterol is a risk factor for ischemic heart disease [2]. ing state. In the Copenhagen City Heart Study stepwise The Prospective Study Collaboration reports that the increasing levels of non-fasting cholesterol and non-fast- relations between cholesterol and CVD holds true across ing triglycerides were similarly associated with stepwise age and blood pressure categories. Interestingly, total/ increasing risk of myocardial infarction, with non-fasting HDL-cholesterol ratio is more informative in this meta- triglycerides being the best predictor in women and non- analysis than high density lipoprotein (HDL), non-HDL or fasting cholesterol the best predictor in men. Surprisingly, total cholesterol. The analysis, however, reported no clear only increasing levels of triglyceride were associated with association between cholesterol and stroke. Stroke is a total mortality whereas increasing cholesterol levels were heterogeneous condition and various causes of ischemic not [10]. Using the same study cohort the authors found stroke may have different associations with cholesterol [3, that stepwise increasing levels of non-fasting triglycerides 4]. By contrast, meta-analysis of randomized trials of few were associated with risk of ischemic stroke in men and years of statin therapy have shown that reduction of LDL women [11, 12]. Increased levels of non-fasting triglycer- cholesterol by about 1.5 mmol/L reduces by about a third ide indicate the presence of increased levels of remnants the incidence not only of ischemic heart disease but also from chylomicrons (CM) and very low density lipoproteins of ischemic stroke, independently of age, blood pressure (VLDL). These cholesterol containing triglyceride rich or prerandomization lipid concentrations. The benefits of lipoproteins can penetrate the arterial endothelium and treatment were significant in the first year, but remained may get trapped within the subendothelial space leading in subsequent years. The reduction in ischemic stroke in to the development of atherosclerosis [13]. Several studies randomized trials of statins suggests a need for more anal- have raised the possibility that remnant particles may be ysis of blood lipids and stroke subtypes [5]. Further meta- associated with CVD risk [14, 15]. In meta-analyses of the analysis of randomized trials comparing more versus less effects of Gly188Glu and Asn291Ser substitutions in lipo- intensive statin therapy suggested that for each 1 mmol/L protein lipase Wittrup et al. [16] reported that in carriers reduction in LDL cholesterol the annual rate of major of both substitutions post-heparin lipoprotein lipase (LPL) Ramasamy: Lipoprotein metabolism 1697 activity was decreased with an increase in plasma triglyc- As there is a need for strict maintenance of tissue cho- erides. Accordingly, the risk of ischemic heart disease was lesterol and triglyceride levels the body relies on a complex increased in heterozygous