1999 George Lyman Duff Memorial Lecture - Lipid transfer proteins, HDL metabolism, and atherogenesis

Plasma high density lipoprotein (HDL) levels show an inverse relationship t o atherogenesis, in part reflecting the role of HDL in mediating reverse ch olesterol transport. The transfer of HDL cholesterol to the liver involves 3 catabolic pathways: the indirect, cholesteryl ester transfer protein (CET P)-mediated pathway, the selective uptake (scavenger receptor BI) pathway, and a particulate HDL uptake pathway. The functions of the lipid transfer p roteins (CETP and phospholipid transfer protein) in HDL metabolism have bee n elucidated by genetic approaches in humans and mice. Human CETP deficienc y is associated with increased HDL levels but appears to increase coronary artery disease risk, Phospholipid transfer protein deficiency, produced by gene knockout in mice, results in decreased HDL levels, reflecting decrease d transfer of phospholipids from triglyceride-rich lipoproteins into HDL. O bese (oblob) mice have markedly increased HDL levels and represent an inter esting model of defective HDL catabolism in the liver. In hepatocytes of wi ld-type mice, there is extensive uptake and resecretion of HDL and selectiv e uptake of cholesteryl ester from HDL during recycling. In oblob mice, the se processes are defective, suggesting that HDL recycling plays an importan t role in holo-HDL catabolism, selective uptake, and the determination of p lasma HDL levels.