Cholesterol and phospholipid metabolism in macrophages

Cholesterol-loaded macrophages are present at all stages of atherogenesis, and recent in vivo data indicate that these cells play important roles in b oth early lesion development and late lesion complications. To understand h ow these cells promote atherogenesis, it is critical that we understand how lesional macrophages interact with subendothelial lipoproteins, the conseq uences of this interaction, and the impact of subsequent intracellular meta bolic events. In the arterial wall, macrophages likely interact with both s oluble and matrix-retained lipoproteins, and a new challenge is to understa nd how certain consequences of these two processes might differ. Initially, the major intracellular metabolic route of the lipoprotein-derived cholest erol is esterification to fatty acids, but macrophages in advanced atherosc lerotic lesions progressively accumulate large amounts of unesterified, or free, cholesterol (FC). In cultured macrophages, excess FC accumulation sti mulates phospholipid biosynthesis, which is an adaptive response to protect the macrophage from FC-induced cytotoxicity. This phospholipid response ev entually decreases with continued FC loading, leading to a series of cellul ar death reactions involving both death receptor-induced signaling and mito chondrial dysfunction. Because macrophage death in advanced lesions is thou ght to promote plaque instability, these intracellular processes involving cholesterol, phospholipid, and death pathways may play a critical role in t he acute clinical manifestations of advanced atherosclerotic lesions. (C) 2 000 Elsevier Science B.V. All rights reserved.