7. Lipid transfer proteins and receptors in HDL metabolism

Abstract

Plasma high density lipoprotein (HDL) levels are determined both by intravascular metabolism and by clearance pathways. Recent evidence indicates that plasma lipid transfer proteins play a major role in the intravascular metabolism of HDL, while HDL receptors in tissues are important in HDL catabolism. The role of the plasma lipid transfer proteins, cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), have been elucidated by genetic deficiency states in humans or mice, or by overexpression experiments in mice. Human CETP deficiency results in increased HDL levels, but also increased coronary heart disease, suggesting an anti-atherogenic function of CETP related to its role in reverse cholesterol transport. PLTP knock-out mice have absent plasma phospholipid transfer activity and markedly reduced HDL cholesterol and apoA-I levels, demonstrating the crucial role that the transfer of surface phospholipid of triglyceride-rich lipoproteins plays in the maintenance of HDL levels. Scavenger receptor BI has recently emerged as an authentic HDL receptor mediating the selective uptake of HDL CE in liver and steroidogenic tissue. Overexpression of SR-BI in transgenic mice results in low HDL levels, and also decreases VLDL and LDL cholesterol and apoB levels, and reduces atherosclerosis in response to a high cholesterol/bile salt diet. Knock-out of SR-BI results in increased HDL levels due to decreased selective uptake in the liver, but the catabolism of HDL proteins is unaltered. Recent studies in obese (ob/ob) mice show a catabolic defect of HDL protein in the liver and suggest a leptin-regulated liver catabolic process for apoA-I and apoA-II. Thus, while CETP, PLTP and SR-BI are important in the turnover of HDL lipids, it appears that distinct receptors are involved in the catabolism of HDL proteins.