Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors

Abstract

Subnormal plasma levels of high-density lipoprotein cholesterol (HDL-C) constitute a major cardiovascular risk factor; raising low HDL-C levels may therefore reduce the residual cardiovascular risk that frequently presents in dyslipidaemic subjects despite statin therapy. Cholesteryl ester transfer protein (CETP), a key modulator not only of the intravascular metabolism of HDL and apolipoprotein (apo) A-I but also of triglyceride (TG)-rich particles and low-density lipoprotein (LDL), mediates the transfer of cholesteryl esters from HDL to pro-atherogenic apoB-lipoproteins, with heterotransfer of TG mainly from very low-density lipoprotein to HDL. Cholesteryl ester transfer protein activity is elevated in the dyslipidaemias of metabolic disease involving insulin resistance and moderate to marked hypertriglyceridaemia, and is intimately associated with premature atherosclerosis and high cardiovascular risk. Cholesteryl ester transfer protein inhibition therefore presents a preferential target for elevation of HDL-C and reduction in atherosclerosis. This review appraises recent evidence for a central role of CETP in the action of current lipid-modulating agents with HDL-raising potential, i.e. statins, fibrates, and niacin, and compares their mechanisms of action with those of pharmacological agents under development which directly inhibit CETP. New CETP inhibitors, such as dalcetrapib and anacetrapib, are targeted to normalize HDL/apoA-I levels and anti-atherogenic activities of HDL particles. Further studies of these CETP inhibitors, in particular in long-term, large-scale outcome trials, will provide essential information on their safety and efficacy in reducing residual cardiovascular risk.

Figure 1

Pathways of reverse cholesterol transport in man. The reverse cholesterol transport system involves lipoprotein-mediated transport of cholesterol from peripheral, extra-hepatic tissues, and arterial tissue (potentially including cholesterol-loaded foam cell macrophages of the atherosclerotic plaque) to the liver for excretion, either in the form of biliary cholesterol or bile acids. The ATP-binding cassette transporters, ABCA1 and ABCG1, and the scavenger receptor B1, are all implicated in cellular cholesterol efflux mechanisms to specific apoA-I/HDL acceptors. The progressive action of lecithin:cholesterol acyl transferase on free cholesterol in lipid-poor, apolipoprotein A-I-containing nascent high-density lipoproteins, including pre-β-HDL, gives rise to the formation of a spectrum of mature, spherical high-density lipoproteins with a neutral lipid core of cholesteryl ester and triglyceride. Mature high-density lipoproteins consist of two major subclasses, large cholesteryl ester-rich HDL2 and small cholesteryl ester-poor, protein-rich HDL3 particles; the latter represent the intravascular precursors of HDL2. The reverse cholesterol transport system involves two key pathways: (a) the direct pathway (blue lines), in which the cholesteryl ester content (and potentially some free cholesterol) of mature high-density lipoprotein particles is taken up primarily by a selective uptake process involving the hepatic scavenger receptor B1, and: (b) an indirect pathway (red lines) in which cholesteryl ester originating in high-density lipoprotein is deviated to potentially atherogenic very low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein particles by cholesteryl ester transfer protein. Both the cholesteryl ester and free cholesterol content of these particles are taken up by the liver predominantly via the low-density lipoprotein receptor which binds their apoB100 component. This latter pathway may represent up to 70% of cholesteryl ester delivered to the liver per day. The hepatic low-density lipoprotein receptor is also responsible for the direct uptake of high-density lipoprotein particles containing apoE; apoE may be present as a component of both HDL2 and HDL3 particles, and may be derived either by transfer from triglyceride-rich lipoproteins, or from tissue sources (principally liver and monocyte-macrophages). Whereas high-density lipoprotein uptake by the low-density lipoprotein receptor results primarily in lysosomal-mediated degradation of both lipids and apolipoproteins, interaction of high-density lipoprotein with scavenger receptor B1 regenerates lipid-poor apoA-I and cholesterol-depleted high-density lipoproteins, both of which may re-enter the HDL/apoA-I cycle. LPL, lipoprotein lipase; PL, phospholipids; HDL-R, holo HDL receptor; HL, hepatic lipase.

Figure 2

Comparison of pathways of cholesteryl ester transfer protein-mediated heterotransfer of neutral core lipids between lipoprotein particles in normotriglyceridaemia vs. mixed dyslipidaemia involving moderate to marked hypertriglyceridaemia and subnormal levels of triglyceride-enriched high-density lipoprotein. In normotriglyceridaemia, net cholesteryl ester transfer from high-density lipoprotein to low-density lipoprotein predominates, with minor transfer to triglyceride-rich lipoproteins. In hypertriglyceridaemic states, increased numbers of very low-density lipoprotein particles constitute preferential cholesteryl ester acceptors giving rise to elevated acceptor capacity for cholesteryl ester transfer protein; high net mass transfer rates of cholesteryl ester from high-density lipoprotein to triglyceride-rich lipoproteins and of triglyceride from triglyceride-rich lipoproteins to both high- and low-density lipoproteins result. Triglyceride enrichment of both high- and low-density lipoproteins by this mechanism gives rise to formation of small dense low-density lipoprotein and small dense high-density lipoprotein. Modified from Barter et al. (with permission from Lippincott Williams and Wilkins).

Figure 3

Cardiovascular risk remains high despite aggressive statin therapy. Statin treatment across a wide range of lipid phenotypes in patients at high cardiovascular risk has been highly successful in reducing relative risk by up to 45%. Nonetheless, major residual cardiovascular risk remains, part of which is due to non-modifiable risk factors but equally to modifiable risk factors. Atherogenic mixed dyslipidaemia is a frequent component of the latter, thereby suggesting that therapeutic attenuation of risk in this phenotype, which involves elevated levels of triglyceride-rich lipoproteins and small dense low-density lipoprotein, with subnormal levels of high-density lipoprotein cholesterol and apoA-I, would contribute to further reduction in residual risk across a wide range of metabolic disease states. ACS, acute coronary syndrome; CHD, coronary heart disease; LDL-C, LDL cholesterol.