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Biochemistry of Atherosclerosis edited by S.K. Cheema, Springer, New York, 2006
2
The Role of LCAT in Atherosclerosis
DOMINIC S. NG
Abstract
Lecithin–cholesterol acyltransferase (LCAT) is one of the major modulators of plasma high-density lipoprotein cholesterol (HDL-C) and plays a central role in the reverse cholesterol transport (RCT) process. Clinically, partial LCAT deficiency is common in a number of chronic disorders at risk for coronary heart diseases (CHD) but the role of LCAT in atherosclerosis remains controversial. Patients with monogenic causes of complete LCAT deficiency appear not to be prone to premature CHD. On the other hand, recent studies on patients with monogenic-based partial LCAT deficiency suggest they may be at increased atherogenic risk. Animal models with transgenic overexpression of the LCAT genes showed variable degrees of antiatherogenic properties except in one transgenic mouse model. LCAT knockout mouse models from different laboratories showed conflicting findings in their predisposition to aortic atherosclerosis. On the other hand, a number of studies using the LCAT knockout mice revealed significant impact of LCAT deficiency on not only lipoprotein metabolism but also in systemic oxidative stress, intrahepatic lipid, and glucose metabolism, each of which may individually modulate atherogenesis. Much remain to be learned with respect to the impact of LCAT deficiency on various proatherogenic pathways to better delineate its pathophysiologic link to atherosclerosis. This is of particular significance in patients suffering from common atherosclerosis-prone disorders that are known to be associated with partial LCAT deficiency, including diabetes and renal insufficiencies.
Keywords: atherosclerosis; high-density lipoprotein (HDL); glomerulopathy; lecithin–cholesterol acyltransferase (LCAT); lipoprotein-X (LpX); triglycerides, glucose
Abbreviations: LCAT, lecithin–cholesterol acyltransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CETP, cholesteryl ester transfer protein; PLTP, phospholipids transfer protein; ABCA1, ATP-binding cassette A1; PC, phosphatidylcholine; SR-BI, scavenger receptor class B type I
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24 Dominic S. NG
Introduction
High-Density Lipoprotein and Atherosclerosis—
Epidemiologic Evidence
Numerous large-scale epidemiological studies persistently demonstrated an inverse relationship between plasma high-density lipoprotein cholesterol (HDL-C) level and the risk of coronary heart disease (CHD). An aggregate analysis of four of the largest US studies, which include the Framingham Heart Study [1], the Lipid Research Clinic Prevalence Mortality Follow-up Study, Lipid Research Clinic Primary Prevention Trial, and Multiple Risk Factor Intervention Trial [2], estimated that each 1 mg/dL (0.02 mmol/L) elevation of HDL-C is associated with a 2–3% reduction in CHD risk, a magnitude comparable to that for low-density lipoprotein (LDL) lowering. While this quantitative relationship may be valid in an epidemiologic context, and may also reflect some biological function of the circulating lipoprotein fraction, the use of a single HDL-C level as a risk predictor require caution. The heterogeneity in the HDL–CHD relationship is best exemplified by studying kindreds with monogenic causes of low HDL-C, namely with mutations in the apolipoprotein apoA-I, lecithin–cholesterol acyltransferase (LCAT), and ATP-binding cassette A1 (ABCA1) genes. Individuals homozygous for mutations in these genes uniformly develop severe HDL deficiency but the affected are not equally at risk of premature CHD. This is particularly the case with patients with complete LCAT deficiency.
The Role of LCAT in HDL Metabolism and Reverse Cholesterol Transport
LCAT was first described as a plasma enzyme, which mediates the transfer of fatty acids at the sn-2 position from phosphatidylcholine (PC) to free cholesterol (FC), forming the neutral lipid cholesterol ester (CE) and lysophosphatidylcholine (LPC) [3]. It is a 416 amino acid glycoprotein synthesized and secreted primarily by the liver. mRNA messages of the LCAT gene have also been detected in testes and the brain [4] but their physiological significance are not well understood.
Upon secretion by the liver, LCAT circulates in plasma bound primarily to HDL but it is also found in apoB-containing lipoproteins, especially the LDL. Kinetic studies in humans have provided an estimate that approximately 70% of plasma CE are formed in the HDL and 30% in the apoB-containing particles [5]. Esterification of FC on apoB-containing particles and HDL by LCAT are coined by the terms β- and α-activity, respectively, and each plays different role in lipoprotein metabolism.
By way of its primary enzymatic action, LCAT plays a major role in HDL metabolism, especially in the reverse cholesterol transport (RCT) pathway, a multistep process by which cholesterol in the peripheral tissues is transferred
Chapter 2. The Role of LCAT in Atherosclerosis |
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back to the liver for eventual elimination from the body (Fig. 2.1). To date, the RCT pathway continues to be considered as one of the major mechanisms by which HDL confers its cardioprotective effects [6]. The first step of RCT entails the efflux of cellular cholesterol, along with phospholipids, onto the cholesterol acceptors, with the lipid-free apoA-I and the disc-shaped pre- β-HDL being most avid [7]. Esterification of tissue-derived FC by LCAT transfers the neutral CE into the lipoprotein core, hence sustaining a chemical gradient to accept more FC from tissues. The accumulation of core CE converts the disc-shaped HDL to spherical particles. The mature HDL can further acquire other apoproteins from triglyceride-rich lipoprotein particles. The mature HDL particles can deliver its CE content directly into the liver through the selective uptake process mediated by scavenger receptor class B type I (SRBI). On the other hand, the tissue-derived CE in HDL can also be transferred to the apoB-containing lipoproteins, in exchange for TG, through the action of
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SR-BI
FIGURE 2.1. Schematics of the reverse cholesterol transport (RCT) pathway and the role of LCAT in HDL metabolism. Key steps in the RCT pathway include (1) cholesterol efflux: the transport of free cholesterol from peripheral cells (e.g., arterial wall macrophages) onto the circulating nascent HDL or lipid-free apoA-I (not shown)— mediated by the ATP-binding cassette AI (ABCA1) transporter; (2) cholesterol esterification: cell-derived cholesterol are esterified by lecithin–cholesterol acyltransferase (LCAT), generating neutral esterified cholesterol (CE) which enters the core; (3) lipid transfer: exchange of CE from HDL with triglyceride-rich lipoproteins for TG— mediated by cholesteryl ester transfer protein (CETP). The CE of the mature HDL can also be taken up directly into the liver—mediated by scavenger receptor class B type I (SR-BI). LPL, lipoprotein lipase; LDL-R, low-density lipoprotein receptor.
26 Dominic S. NG
cholesteryl ester transfer protein (CETP). When the apoB-containing lipoproteins are taken up by the liver, the tissue-derived cholesterol can be channeled for elimination from the body through the biliary cholesterol pathway [8].
More recently, Nakamura et al. [9] examined the differential efficiency of LCAT activity in the generation of CE in various HDL fractions. These authors reported LCAT is associated with various size fractions of HDL and the smallest HDL identified in this experimental regime is consistent with a pre-β-HDL/LCAT complex. Among the various size fractions, the small pre- β-HDL-associated LCAT was responsible for the majority of the LCATmediated esterification of CE in HDL. Furthermore, these authors also examined the role of HDL size on the activity of CETP and reported a preferential transfer of CE from the small HDL fractions, including those derived from the pre-β-HDL. Continued activity of LCAT leads to the “maturation” and formation of the α-migrating HDL. Meanwhile, the larger HDL are subject to the modulatory action of phospholipids transfer protein (PLTP), replenishing the pool of pre-β-HDL. In this paradigm, one could envision a pool of HDL that would recycle between the smaller “metabolically active” form and the more mature form, and the cycle will continue to fuel the net movement of cell-derived cholesterol towards the liver for removal.
LCAT is one of the several major modulators of the plasma HDL-C levels, the other being apoA-I, ABCA1, and CETP. In humans subjects with genetic deficiency of LCAT, those who are homozygous a functional LCAT gene mutation develop severe HDL deficiency and the ones heterozygous for a defective LCAT gene develop intermediate levels of HDL deficiency [10, 11]. The marked reduction in HDL-C in the LCAT deficient subjects is attributed primarily to an accelerated catabolism of the HDL particles, with those containing apoA-I and apoA-II being more rapidly cleared than those containing apoA-I alone [12]. The residual circulating lipoproteins in the HDL density range include (a) the discoidal particles containing apoA-I, apoA-II, and occasionally apoE which often form rouleaux and (b) the small apoA-I containing particles that are rich in FC and PL. Interestingly, plasma from LCAT deficient subjects have been demonstrated to be equally effective in mediated cholesterol efflux in fibroblasts [13] but this finding was not shared by other [14, 15]. It is tempting to postulate that the residual HDL in LCAT deficient subjects are functionally sufficient for the majority of the esterification of the cell-derived cholesterol [9] although confirmatory evidence is lacking.
LCAT and Atherosclerosis—Clinical Studies
Monogenic Disorders—Humans
The human LCAT gene is located in the q12–22 region of chromosome 16. Up until recently, 40 mutations have been reported (HGMD; http://uwcmml1s. uwcm.ac.uk/mg/search/119359.html). Calabresi et al. [11] reported an additional
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15 novel mutations more recently. In addition to a marked reduction in HDL-C, other lipoprotein phenotypes in homozygotes and compound heterozygotes further distinguish the LCAT mutations into two distinct syndromes, the complete LCAT deficiency (CLD) and the fish-eye disease (FED). The CLD is characterized by a complete or near-complete deficiency of LCAT activity in the plasma with the absence of cholesterol esterification in all lipoprotein classes. Furthermore, marked increase in total plasma FC/CE ratio and an accumulation of the phospholipid precursor are also hallmarks of the CLD syndrome. Clinically, despite the disruption of the RCT pathway and the severe low level of HDL-C, CLD subjects are paradoxically not particularly predisposed to premature CHD [10, 16–18]. Instead, there is a high prevalence of glomerulopathy in these subjects [19]. Other phenotypes include modest hypertriglyceridemia (HTG), presence of LpX vesicles and mild anemia [20]. In FED, LCAT activity is absent selectively in the HDL fractions. In these subjects, HDL-C is markedly reduced but cholesterol esterification in the apoB-containing lipoprotein particles is relatively preserved. FED patients are not associated with renal complications. However, a number of FED mutations had been found to be associated with premature coronary artery disease (CAD) [21, 22] but the underlying pathogenesis remains obscure.
Although subjects with complete LCAT deficiency appear to be associated with a paradoxical absence of premature CAD in spite of severe HDL deficiency, little is known about the predisposition of partial LCAT deficient subjects based on earlier studies. More recently, Ayyobi et al. [23] reported a 25-year longitudinal follow-up of a large Canadian LCAT deficient kindred concerning their vascular risk. Carotid ultrasound for intima-medial thickness (IMT) and brachial artery flow-mediated dilatation (FMD) were used as surrogate markers for cardiovascular endpoints. These authors reported that, based on two homozygotes, nine heterozygotes, and four unaffected family members, the heterozygotes are associated with pronounced IMT abnormalities including detection of atherosclerotic plaques whereas for the homozygotes, the IMT are only minimally increased. A similar vascular evaluation by IMT in 68 carriers of various known FED mutations showed significant increase in IMT progression in both heterozygotes and homozygotes [24].
Putting it all together, data from families with genetic causes of LCAT deficiency suggest that FED mutations may confer higher risk of CAD than those with CLD. On the other hand, subjects homozygous for CLD mutations are generally not at risk of accelerated CAD but the heterozygotes with partial LCAT deficiency, appear to be more prone. In light of the clinical observations that partial LCAT deficiency being detected in a variety of common diseases known to be at high risk of premature CAD, e.g., diabetes [25, 26], uremia [27], cigarette smoking [28] etc., the proatherogenic potential of partial LCAT deficiency require confirmation as this would form the basis for LCAT being a potential therapeutic target.