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Review
, 59 (5), 772-783

Cholesteryl Ester Transfer Protein and Its Inhibitors

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Review

Cholesteryl Ester Transfer Protein and Its Inhibitors

Sudichhya Shrestha et al. J Lipid Res.

Abstract

Most of the cholesterol in plasma is in an esterified form that is generated in potentially cardioprotective HDLs. Cholesteryl ester transfer protein (CETP) mediates bidirectional transfers of cholesteryl esters (CEs) and triglycerides (TGs) between plasma lipoproteins. Because CE originates in HDLs and TG enters the plasma as a component of VLDLs, activity of CETP results in a net mass transfer of CE from HDLs to VLDLs and LDLs, and of TG from VLDLs to LDLs and HDLs. As inhibition of CETP activity increases the concentration of HDL-cholesterol and decreases the concentration of VLDL- and LDL-cholesterol, it has the potential to reduce atherosclerotic CVD. This has led to the development of anti-CETP neutralizing monoclonal antibodies, vaccines, and antisense oligonucleotides. Small molecule inhibitors of CETP have also been developed and four of them have been studied in large scale cardiovascular clinical outcome trials. This review describes the structure of CETP and its mechanism of action. Details of its regulation and nonlipid transporting functions are discussed, and the results of the large scale clinical outcome trials of small molecule CETP inhibitors are summarized.

Keywords: atherosclerosis; lipid transfers; lipoproteins.

Figures

Fig. 1.
Fig. 1.
CETP-mediated transfers of neutral lipids between different lipoproteins. CETP transfers CEs and TGs between HDLs, VLDLs, and LDLs.
Fig. 2.
Fig. 2.
Mechanism of action of CETP. CETP transfers CEs and TGs between HDLs and other lipoproteins by a shuttle mechanism (A) or by forming a bridging complex between HDL and another lipoprotein (VLDL is shown) (B).
Fig. 3.
Fig. 3.
Structures of small molecule CETP inhibitors. Chemical structures for torcetrapib (A), dacetrapib (B), evacetrapib (C), anacetrapib (D), and TA-8995 (E) are shown.

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