Phospholipid transfer protein and atherosclerosis: genetic studies take aim at a moving target.

Phospholipid transfer protein (PLTP) is a member of the lipid transfer/lipopolysaccharide-binding protein family that first attracted attention by virtue of its functions in intravascular lipoprotein metabolism. These include its key role in mediating transfer of phospholipids from very-lowdensity lipoprotein to high-density lipoprotein (HDL) in conjunction with very-low-density lipoprotein lipolysis and its capacity to remodel HDL by promoting the production of larger HDL through fusion of 2 smaller particles with generation of lipid-poor apolipoprotein (apo) AI.1 The latter has properties consistent with pre1 HDL, a species that can contribute to cellular cholesterol efflux2 and plays a role in reverse cholesterol transport. Together with evidence that PLTP levels are correlated with plasma concentrations of HDL cholesterol and apoAI,3 these properties of PLTP led to the suggestion that it may have an atheroprotective role; however, an increasing body of evidence from animal and human studies has pointed to its proatherogenic effects. In apoB-transgenic and apoE-deficient mice, PLTP deficiency resulted in markedly decreased atherosclerosis,4 whereas in PLTP-transgenic mice, atherosclerosis was increased5 and macrophage cholesterol efflux and reverse cholesterol transport were impaired.6 Moreover, macrophages were shown to be a source of plasma PLTP,7 and bone marrow transplantation of cells overexpressing PLTP into low-density lipoprotein-receptor–null mice resulted in proatherogenic lipid changes and increased atherosclerosis.8 On the other hand, atherosclerosis was decreased by bone marrow transplantation of macrophages expressing PLTP in double low-density lipoprotein-receptor– and PLTP-deficient mice, in conjunction with reduced plasma total cholesterol and increased HDL.9 Thus, it appears that systemic PLTP has proatherogenic effects, although in some circumstances, macrophagederived PLTP may be atheroprotective.