Kevin C. Glenn

Inhibition of cholesteryl ester transfer protein by apolipoproteins, lipopolysaccharides, and cholesteryl sulfate

Cholesteryl ester transfer protein (CETP) mediates the exchange of cholesteryl esters and triglycerides between lipoproteins in the plasma. In studies dealing with the mechanism of CETP-mediated lipid transfer, we have examined the effects of several classes of biomolecules, including apolipoproteins and related synthetic peptides, cholesteryl sulfate, and lipopolysaccharides. In all cases, the molecules were inhibitory and their effects were associated with modifications of either HDL, LDL, or both. However, the probable mechanisms were distinct for each class of inhibitor. Inhibition of lipid transfer activity by apolipoprotein A-I was correlated with an increase in the apolipoprotein A-I content of HDL but not LDL, whereas the primary effect of cholesteryl sulfate was associated with modification of LDL, and only modest alteration of HDL. Lipopolysaccharides were found to modify the size and charge properties of both LDL and HDL over the same concentration ranges that affected CETP activity, but might also interact directly with CETP. It is suggested from the present studies that a variety of biomolecules that can interact with lipoproteins under natural or pathological situations have the potential to modify CETP activity, which in turn could affect normal lipoprotein composition and distribution.

Chapter 22. Cholesteryl ester transfer protein as a potential therapeutic target to improve the HDL to LDL cholesterol ratio

Publisher Summary This chapter analyzes cholesteryl ester transfer protein (CETP) as a potential therapeutic target to improve the high density lipoprotein (HDL) to low density lipoprotein (LDL) cholesterol ratio. CETP mediates the transfer of cholesteryl esters (CE) from HDL to VLDL with a balanced reciprocal exchange of TG. CETP moves CE from HDL that is known to protect against coronary heart disease (CHD) into proatherogenic VLDL and LDL. Studies support the theory that CETP is atherogenic. More recently, data from transgenic mouse studies and detailed evaluation of human genetic epidemiology suggest CETP may also be able to serve a protective role against CHD. CETP may be cardio-protective by its participation in a process termed “reverse cholesterol transport” (RCT), that is, the transfer of cholesterol from peripheral tissues to the liver via HDL. Species variation in CETP expression correlates with their HDL-C levels and susceptibility to dietary cholesterol-induced atherosclerosis. The chapter discusses inhibition of CETP as a therapeutic target. Chemistry of small molecule CETP inhibitors is explained and an overview of tetrahydroquinoline and tetrahydronaphthalene inhibitors is also presented.