Apolipoprotein-mediated removal of cellular cholesterol and phospholipids

Abstract

It is widely believed that high density lipoprotein (HDL) protects against cardiovascular disease by removing excess cholesterol from cells of the artery wall. Recent cell culture studies have provided evidence that a major pathway for removing cholesterol and phospholipids from cells is mediated by the direct interactions of HDL apolipoproteins (apo) with plasma membrane domains. These interactions efficiently clear cells of excess sterol by targeting for removal pools of cholesterol that feed into the cholesteryl ester cycle. The precursors for this pathway in vivo are likely to be lipid-free or lipid-poor apolipoproteins generated either by dissociation from the surface of HDL particles or by de novo synthesis. Fibroblasts from subjects with a severe HDL deficiency syndrome called Tangier disease have a cellular defect that prevents apolipoproteins from removing both cholesterol and phospholipids from cells. This defect is associated with a near absence of plasma HDL, markedly below normal low density lipoprotein (LDL) levels, and the appearance of macrophage foam cells in tissues. Thus, an inability of nascent apoA-I to acquire cellular lipids results in a rapid clearance of apoA-I from the plasma, decreased production and increased clearance of LDL, and sterol deposition in tissue macrophages. Although the molecular properties of this pathway are still poorly understood, these studies imply that the apolipoprotein-mediated pathway for removal of cellular lipids is a major source of plasma cholesterol and phospholipids and plays an important role in clearing excess cholesterol from macrophages in vivo.