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

Abstract

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.

• Authors: Lei Lei, Ying Xiong, Jia Chen, Jin-Bo Yang, Yi Wang, Xin-Ying Yang, Catherine C Y Chang, Bao-Liang Song, Ta-Yuan Chang, Bo-Liang Li
• Journal: Journal of lipid research (J Lipid Res) Vol. 50 Issue 6 Pg. 1057-67 (Jun 2009) ISSN: 0022-2275 [Print] United States
• PMID: 19189937 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cholesterol Esters
• DNA Primers
• NF-kappa B
• Tumor Necrosis Factor-alpha
• DNA
• ACAT1 protein, human
• Acetyl-CoA C-Acetyltransferase

Topics

• Acetyl-CoA C-Acetyltransferase (genetics, metabolism)
• Atherosclerosis (etiology)
• Base Sequence
• Cell Differentiation
• Cell Line
• Cells, Cultured
• Cholesterol Esters (metabolism)
• DNA (genetics)
• DNA Primers (genetics)
• Gene Expression (drug effects)
• Humans
• Monocytes (cytology, drug effects, metabolism)
• NF-kappa B (metabolism)
• Promoter Regions, Genetic
• Tumor Necrosis Factor-alpha (pharmacology)