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The Side Effects of CETP Inhibition

Cholesteryl ester transfer protein (CETP) is a plasma protein that facilitates the transport of cholesteryl ester and triglyceride between lipoproteins. The protein picks up triglycerides from very low or low density lipoproteins (VLDL or LDL) and can exchange them for cholesteryl esters from high density lipoproteins (HDL) (and vice versa). Because HDL has a protective function in atherosclerosis and cardiovascular disease, the pharmacological inhibition of CETP has been investigated as a way to raise HDL levels.

Triglyceride levels in CETP-deficient cells (B) are lower than in wild-type cells (A).

In this Paper of the Week, Lahoucine Izem and Richard E. Morton use antisense CETP cDNA to suppress expression of the protein in adipocytes and document, for the first time, the importance of intracellular CETP in lipid transport and storage. They show that CETP deficiency affects the translocation of cholesteryl esters and triglycerides from the endoplasmic reticulum to their storage sites. With the extensive recent interest in raising HDL levels through CETP inhibition, the results of this study suggest that an increase in cellular cholesteryl ester storage may be one potential mechanism contributing to the adverse effects of CETP inhibitors such as Pfizer's torcetrapib.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 21856-21865

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