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

• Published in: Journal of lipid research 2009-06, Vol.50 (6), p.1057-1067
• Main Authors: Lei, Lei, Xiong, Ying, Chen, Jia, Yang, Jin-Bo, Wang, Yi, Yang, Xin-Ying, Chang, Catherine C.Y., Song, Bao-Liang, Chang, Ta-Yuan, Li, Bo-Liang
• Format: Article
• Language: English
• Subjects: Acetyl-CoA C-Acetyltransferase - genetics; Acetyl-CoA C-Acetyltransferase - metabolism; atherosclerosis; Atherosclerosis - etiology; Base Sequence; Cell Differentiation; Cell Line; Cells, Cultured; cholesterol esterification; Cholesterol Esters - metabolism; DNA - genetics; DNA Primers - genetics; Gene Expression - drug effects; Humans; inflammatory cytokine; lipid metabolism; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; NF-kappa B - metabolism; Promoter Regions, Genetic; transcription control; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M800484-JLR200

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.