Targeting Cholesteryl Ester Transfer Protein for the Prevention and Management of Cardiovascular Disease
Philip J. Barter, MBBS, PhD, FRACP*,* and
John J.P. Kastelein, MD, PhD
* The Heart Research Institute, Sydney, Australia
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
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Figure 1 Role of cholesteryl ester transfer protein (CETP) in plasma lipid transport. Cholesteryl ester transfer protein promotes bidirectional transfers (shown by the red arrows) of cholesteryl esters (CE) and triglycerides (TG) between high-density lipoproteins (HDLs), very low-density lipoproteins (VLDLs), and low-density lipoproteins (LDLs). Most of the CEs in plasma originate in HDLs in a reaction catalyzed by lecithin:cholesterol acyltransferase (LCAT), while the majority of the TG enters plasma as a component of TG-rich lipoproteins secreted either from the liver as VLDLs or from the intestine as chylomicrons. Very low-density lipoproteins are subsequently converted into LDLs after hydrolysis of a proportion of their TG by lipoprotein lipase (LPL) and hepatic lipase (HL). The overall effect of the CETP-mediated CE exchanges between these lipoproteins is a net mass transfer of CE from the antiatherogenic HDLs to the potentially proatherogenic VLDLs and LDLs. The cholesterol in LDLs is taken up by all cells (both in liver and peripheral tissues) that express the LDL receptor. Modified (oxidized) LDLs are also taken up by macrophages in a scavenger receptor-mediated process that converts the macrophage into a foam cell. Cholesterol, both in its free or unesterified form (FC) and in its esterified form as CE, is returned to the liver by HDLs via the scavenger receptor-B1 (SR-B1) (pathway 1) and by LDLs via the LDL receptor (LDL-R) (pathway 2). See Figure 2 for mechanisms through which peripheral cells may efflux cholesterol to HDL particles.
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Figure 2 Efflux of cholesterol from peripheral cells. High-density lipoprotein (HDL) particles may accept free cholesterol (FC) from peripheral cells via several mechanisms. The ATP-binding cassette transporter A1 (ABCA1) effluxes FC to lipid-poor apolipoprotein (apo) A1 resulting in the formation of discoidal, nascent HDL. Esterification of the FC in nascent HDL by lecithin:cholesterol acyltransferase (LCAT) generates spherical, mature HDL particles. The lipidation of lipid-poor apo A1 and the conversion of discoidal HDL to spherical particles are rapid as evidenced by the very low levels of lipid-poor apo A1 and discoidal HDL in normal plasma. Free cholesterol may be effluxed to mature HDL particles by passive diffusion or by a receptor-mediated pathway, including the scavenger receptor B-1 (SR-B1) or the newly identified ATP-binding cassette transporter G1 (ABCG1). PL = phospholipid.
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Figure 3 Effect of cholesteryl ester transfer protein (CETP) on lipoprotein particle size. Cholesteryl ester transfer protein mediates the transfer of triglycerides (TG) from TG-rich lipoproteins to high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in exchange for cholesteryl esters (CE). Through the action of TG lipases, HDL particles decrease in size and apolipoprotein (Apo) A1 dissociates from HDL. Although dissociated Apo A1 may be reused in the first step of reverse cholesterol transport as an acceptor of cholesterol effluxed from cells, it may also be lost by renal clearance. Triglyceride lipases similarly reduce the size of LDL particles. The resultant small, dense LDL is more susceptible to oxidation and subsequent uptake by arterial macrophages. VLDL = very low-density lipoprotein.
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