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

Lei Lei^*, Ying Xiong^*, Jia Chen^*, Jin-Bo Yang^*, Yi Wang^*, Xin-Ying Yang^*, Catherine C. Y. Chang, Bao-Liang Song^*, Ta-Yuan Chang and Bo-Liang Li¹^,*

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

This work was supported by grants from the Ministry of Scienceand Technology of China (No. 2006CB910600, 2009CB919000), theNational Natural Science Foundation of China (No. 30571057,30623002), and Shanghai Science and Technology Committee (No.07JC14061, 08431900500) (B-L.L., B-L.S., and Y.X.), and by NationalInstitutes of Health Grant HL-60306 to T-Y.C.).

Published, JLR Papers in Press, February 2, 2009.

^¹ To whom correspondence should be addressed. e-mail: blli{at}sibs.ac.cn

High levels of the inflammatory cytokine tumor necrosis factor- ${alpha}$ (TNF- ${alpha}$ ) are present in atherosclerotic lesions. TNF- ${alpha}$ regulatesexpression 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 ofatherosclerosis. We hypothesize that TNF- ${alpha}$ may be involved inregulating the ACAT gene expression in monocytes/macrophages.In this article, we show that in cultured, differentiating humanmonocytes, TNF- ${alpha}$ enhances the expression of the ACAT1 but notACAT2 gene, increases the cholesteryl ester accumulation, andpromotes the lipid-laden cell formation. Several other proinflammatorycytokines tested do not affect the ACAT1 gene expression. Thestimulation 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 locatedwithin the human ACAT1 gene proximal promoter is required tomediate the action of TNF- ${alpha}$ . Our data demonstrate that TNF- ${alpha}$ ,through the NF-kappa B pathway, specifically enhances the expressionof human ACAT1 gene to promote the CE-laden cell formation fromthe differentiating monocytes, and our data support the hypothesisthat TNF- ${alpha}$ is proatherosclerotic during early phase of lesiondevelopment.

Supplementary key words atherosclerosis • cholesterol esterification • inflammatory cytokine • lipid metabolism • transcription control

Abbreviations: ACAT, acyl-coenzyme A:cholesterol acyltransferase; AP-1, activator protein-1; ATRA, all-trans retinoic acid; CE, cholesteryl ester; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GM-CSF, granulocyte-macrophage colony stimulating factor; IFN- ${gamma}$ , interferon-gamma; I ${kappa}$ B ${alpha}$ , inhibitor of NF- ${kappa}$ B-alpha; IL-1β, interleukin-1-beta; IL-6, interleukin-6; IL-10, interleukin-10; LPDS, lipoprotein-deficient serum; LPS, lipopolysaccharide; MCP-1, monocyte chemotactic protein-1; M-CSF, macrophage-colony stimulating factor; NE, nuclear extract; NF- ${kappa}$ B, nuclear factor-kappa B; oxLDL, oxidized low density lipoprotein; PGA1, prostaglandin A₁; PGJ2, 15-deox- ${Delta}$ ^{12, 14}-prostaglandin J₂; Sp1, specificity protein 1; TNF ${alpha}$ , tumor necrosis factor-alpha

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