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Journal of Lipid Research
Year: 2009  |  Volume: 50  |  Issue: 6  |  Page No.: 1057 - 1067

TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation

L Lei, Y Xiong, J Chen, J. B Yang, Y Wang, X. Y Yang, C. C. Y Chang, B. L Song, T. Y Chang and B. L. Li    

Abstract:

High levels of the inflammatory cytokine tumor necrosis factor- (TNF-) are present in atherosclerotic lesions. TNF- regulates expression of multiple genes involved in various stages of atherosclerosis, and it exhibits proatherosclerotic and antiatherosclerotic properties. ACAT catalyzes the formation of cholesteryl esters (CE) in monocytes/macrophages, and it promotes the foam cell formation at the early stage of atherosclerosis. We hypothesize that TNF- may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF- enhances the expression of the ACAT1 but not ACAT2 gene, increases the cholesteryl ester accumulation, and promotes the lipid-laden cell formation. Several other proinflammatory cytokines tested do not affect the ACAT1 gene expression. The stimulation effect is consistent with a receptor-dependent process, and is blocked by using nuclear factor-kappa B (NF-kappa B) inhibitors. A functional and unique NF-kappa B element located within the human ACAT1 gene proximal promoter is required to mediate the action of TNF-. Our data demonstrate that TNF-, through the NF-kappa B pathway, specifically enhances the expression of human ACAT1 gene to promote the CE-laden cell formation from the differentiating monocytes, and our data support the hypothesis that TNF- is proatherosclerotic during early phase of lesion development.

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