Phospholipidation of HDL—How Much Is Too Much?

Abstract

Phospholipid transfer protein (PLTP)2 is a secreted lipid transfer protein that mediates the exchange of phospholipids between lipoproteins in the circulation. By shuttling phospholipid surface remnants generated during triglyceride-rich lipoprotein lipolysis to HDL, PLTP plays an important role in HDL maturation. In addition to forming the phospholipid shell of the particle, PLTP-derived phospholipids serve as a substrate for lecithin-cholesteryl acyltransferase, which generates cholesteryl esters to form the neutral lipid core. PLTP also promotes remodeling and rearrangement of HDL in a process known as “HDL conversion.” In the presence of human apolipoprotein AI (apo AI), PLTP promotes the fusion of smaller HDL3 particles to generate larger HDL2 particles, along with the simultaneous shedding of lipid-poor apo AI. In doing so, PLTP-mediated HDL conversion promotes the regeneration of pre-β HDL. Our references are limited because of space limitations; for a more detailed review of the PLTP literature, please consult one of the excellent review articles on this topic (1, 2). PLTP-deficient mice have major reductions in HDL cholesterol (HDL-C) concentrations and a shift toward smaller HDL particle size that are reflective of the critical role for this protein in HDL metabolism. Paradoxically, substantial overproduction of PLTP in mice also reduces HDL-C concentrations by destabilizing the particles and promoting their catabolism. In the presence of human apo AI, however, modest overproduction of human PLTP has been shown to increase HDL-C and pre-β HDL values, possibly by providing phospholipid as a lecithin-cholesteryl acyltransferase substrate and promoting HDL maturation. In addition to its effects on HDL metabolism, PLTP production has profound effects on the concentrations of apo B lipoproteins. PLTP-deficient mice have lower concentrations of apo B lipoproteins, and small-molecule inhibition of PLTP decreases apo B secretion from hepatocytes. It appears that hepatic PLTP plays an important role in phospholipidation …