PLASMA-LIPID TRANSFER PROTEINS, HIGH-DENSITY-LIPOPROTEINS, AND REVERSE CHOLESTEROL TRANSPORT

Cholesteryl ester transfer protein (CETP) and phospholipid transfer pr otein (PLTP) are members of the lipid transfer/lipopolysaccharide bind ing protein gene family. Recently, the crystal structure of one of the members of the gene family, bactericidal permeability increasing prot ein, was solved, providing potential insights into the mechanisms of a ction of CETP and PLTP. These molecules contain intrinsic lipid bindin g sites and appear to act as carrier proteins that shuttle between lip oproteins to redistribute lipids. The phenotype of human CETP genetic deficiency states and CETP transgenic mice indicates that CETP plays a major role in the catabolism of high-density lipoprotein (HDL) choles teryl esters and thereby influences the concentration, apolipoprotein content, and size of HDL particles in plasma. PLTP also appears to hav e an important role in determining HDL levels and speciation. Recent d ata indicate that genetic CETP deficiency is associated with an excess of coronary heart disease in humans, despite increased HDL levels. Al so, CETP expression is anti-atherogenic in many mouse models, even whi le lowering HDL. These data tend to support the reverse cholesterol tr ansport hypothesis, i.e. that anti-atherogenic properties of HDL are r elated to its role in reverse cholesterol transport. Recently, another key molecule involved in this pathway was identified, scavenger recep tor BI; this mediates the selective uptake of HDL cholesteryl esters i n the liver and thus constitutes a pathway of reverse cholesterol tran sport parallel to that mediated by CETP. Reflecting its role in revers e cholesterol transport, the CETP gene is up-regulated in peripheral t issues and liver in response to dietary or endogenous hypercholesterol emia. An analysis of the CETP proximal promoter indicates that it cont ains sterol regulatory elements highly homologous to those present in 3-hydroxy-3-methylglutaryl-coenzyme A reductase; the CETP gene is tran sactivated by the binding of SREBP-1 to these elements. A challenge fo r the future will be the manipulation of components of the reverse cho lesterol transport pathway, such as CETP, PLTP, or scavenger receptor BI for therapeutic benefit.