期刊
JOURNAL OF LIPID RESEARCH
卷 50, 期 6, 页码 1057-1067出版社
ELSEVIER
DOI: 10.1194/jlr.M800484-JLR200
关键词
atherosclerosis; cholesterol esterification; inflammatory cytokine; lipid metabolism; transcription control
资金
- Ministry of Science and Technology of China [2006CB910600, 2009CB919000]
- National Natural Science Foundation of China [30571057, 30623002]
- Shanghai Science and Technology Committee [07JC14061, 08431900500]
- National Institutes of Health [HL-60306]
High levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are present in atherosclerotic lesions. TNF-alpha 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-alpha may be involved in regulating the ACAT gene expression in monocytes/macrophages. In this article, we show that in cultured, differentiating human monocytes, TNF-alpha 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-alpha. Our data demonstrate that TNF-alpha, 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-alpha is proatherosclerotic during early phase of lesion development.-Lei, L., 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. TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation. J. Lipid Res. 2009. 50: 1057-1067.
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