ATP-binding cassette transporter A1 (ABCA1) in macrophages: A dual function in inflammation and lipid metabolism?

Activated lipid-laden macrophages in the vascular wall are key modulators o f the inflammatory processes underlying atherosclerosis. We demonstrate her e that the ATP-binding cassette (ABC) transporter ABCA1 is induced during d ifferentiation of human monocytes into macrophages. ABCA1 has been implicat ed in macrophage interleukin-lp secretion and apoptosis. Moreover, ABCA1 mR NA and protein levels are strongly upregulated by uptake of modified LDL an d downregulated by HDL3-mediated lipid efflux in macrophages. Mutation anal ysis in patients with the classical Tangier disease (TD), a monogenetic dis order characterized by hypersplenism, macrophage accumulation and depositio n of cholesteryl esters in the reticuloendothelial system, low plasma HDL a nd premature atherosclerosis, revealed deleterious mutations in their ABCA1 gene. The localization pattern of the mutations within the ABCA1 protein a ppears to determine the tropism for either the reticuloendothelial system, as seen in the classical TD phenotype, or the artery wall, as in the case o f HDL deficiency in the absence of splenomegaly. In a comprehensive analysi s of the expression and regulation of all currently known human ABC transpo rters, we identified additional cholesterol-responsive genes that are induc ed during monocyte differentiation into macrophages, Our results indicate a dual regulatory function for ABCA1 in macrophage lipid metabolism and infl ammation. Copyright (C) 2000 S. Karger AG, Basel.