TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation.
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
Lei
L
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Xiong
Ying
Y
Chen
Jia
J
Yang
Jin-Bo
JB
Wang
Yi
Y
Yang
Xin-Ying
XY
Chang
Catherine C Y
CC
Song
Bao-Liang
BL
Chang
Ta-Yuan
TY
Li
Bo-Liang
BL
D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002788:Cholesterol Esters; D017931:DNA Primers; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase