High-Density Lipoprotein Therapies-Then and Now

High-density lipoproteins (HDLs) are antiatherogenic through their role in reverse cholesterol transport (RCT), that is, the transfer of cholesterol from macrophages in the subendothelial space of the arterial wall to HDL carriers to the liver for disposal. Many mechanisms that increase HDL are not atheroprotective; enhancing RCT via improved cholesterol efflux or esterification is not clearly atheroprotective. Only the final RCT step, cholesterol disposal to liver via scavenger receptor class B, Type I (SR-BI) by reducing plasma HDL-C concentrations, seems to atheroprotect. This chapter discusses two major points. First, a low plasma HDL-C concentration is associated with increased cardiovascular disease. Second, central fat is strongly associated with increased cardiovascular disease. It deals with discovery of compounds superior to PPARγ agonists that promote fat storage in noncentral fat depots without promoting weight gain, and the identification of the underlying cause of age-dependent insulin resistance in noncentral fat depots.