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

Journal of Lipid Research

Jin-Bo Yang¹  Bao-Liang Song¹  Ying Xiong¹  Xin-Ying Yang¹  Bo-Liang Li¹  Yi Wang²  Catherine C.Y. Chang²  Lei Lei²  Jia Chen²  Ta-Yuan Chang² 

[1] Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03756;State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

关键词: atherosclerosis;    cholesterol esterification;    inflammatory cytokine;    lipid metabolism;    transcription control;   

DOI  :  

来源: DOAJ

【 摘 要 】

High levels of the inflammatory cytokine tumor necrosis factor-α (TNF-α) are present in atherosclerotic lesions. TNF-α 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-α may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-α 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-α. Our data demonstrate that TNF-α, 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-α is proatherosclerotic during early phase of lesion development.

【 授权许可】

Unknown