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 both early lesion development and late lesion complications. To understand how these cells promote atherogenesis, it is critical that we understand how lesional macrophages interact with subendothelial lipoproteins, the consequences of this interaction, and the impact of subsequent intracellular metabolic events. In the arterial wall, macrophages likely interact with both soluble and matrix-retained lipoproteins, and a new challenge is to understand how certain consequences of these two processes might differ. Initially, the major intracellular metabolic route of the lipoprotein-derived cholesterol is esterification to fatty acids, but macrophages in advanced atherosclerotic lesions progressively accumulate large amounts of unesterified, or free, cholesterol (FC). In cultured macrophages, excess FC accumulation stimulates phospholipid biosynthesis, which is an adaptive response to protect the macrophage from FC-induced cytotoxicity. This phospholipid response eventually decreases with continued FC loading, leading to a series of cellular death reactions involving both death receptor-induced signaling and mitochondrial dysfunction. Because macrophage death in advanced lesions is thought to promote plaque instability, these intracellular processes involving cholesterol, phospholipid, and death pathways may play a critical role in the acute clinical manifestations of advanced atherosclerotic lesions.
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Department of Medicine and Anatomy, Columbia University, 630 West 168th Street, New York, NY, 10032, USA. iat1@columbia.edu
D000818:Animals; D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology*; D002784:Cholesterol / Q000378:metabolism*; D004705:Endocytosis; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D009336:Necrosis; D010743:Phospholipids / Q000096:biosynthesis*
D010743:Phospholipids; D002784:Cholesterol