Jing Ge and Wei Zhai contribute equally to this work.
Insulin induces human acyl-coenzyme A: cholesterol acyltransferase1 gene expression via MAP kinases and CCAAT/enhancer-binding protein α
Article first published online: 18 JUL 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 114, Issue 9, pages 2188–2198, September 2013
How to Cite
Ge, J., Zhai, W., Cheng, B., He, P., Qi, B., Lu, H., Zeng, Y. and Chen, X. (2013), Insulin induces human acyl-coenzyme A: cholesterol acyltransferase1 gene expression via MAP kinases and CCAAT/enhancer-binding protein α. J. Cell. Biochem., 114: 2188–2198. doi: 10.1002/jcb.24568
- Issue published online: 18 JUL 2013
- Article first published online: 18 JUL 2013
- Accepted manuscript online: 8 APR 2013 05:52AM EST
- Manuscript Accepted: 2 APR 2013
- Manuscript Received: 28 NOV 2012
- National Natural Scientific Foundation of China. Grant Number: 30471921
- INSULIN RESISTANCE;
- SIGNAL TRANSDUCTION;
- INSULIN RESPONSIVE ELEMENT
Insulin resistance characterized by hyperinsulinemia is associated with increased risk of atherosclerosis. Acyl-coenzyme A: cholesterol acyltransferase (ACAT) is an intracellular enzyme involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation. To investigate the relationship between hyperinsulinemia and atherosclerosis, we investigated whether insulin induced ACAT1 gene expression and found that insulin up-regulated ACAT1 mRNA, protein and enzyme activity in human THP-1 cells and THP-1–derived macrophages. Moreover, luciferase assays revealed that insulin enhanced the ACAT1 gene P1 promoter activity but not the P7 promoter. To explore the molecular mechanisms involved, deletion analysis of the human ACAT1 P1 promoter revealed an insulin response element (IRE) upstream of the P1 promoter (from −603 to −580), EMSA experiments demonstrated that CCAAT/enhancer binding protein α(C/EBPα) bound to the P1 promoter IRE. Insulin-induced ACAT1 upregulation was blocked by the presence of PD98059 (an inhibitor of extracellular signal-regulated kinase, ERK) and SB203580 (an inhibitor of p38 mitogen-activated protein kinase, p38MAPK) but not by Wortmannin (an inhibitor of phosphatidylinositol 3-kinase, PI3K) or U73122 (an inhibitor of phospholipase C-γ, PLCγ). These studies demonstrate that insulin promotes ACAT1 gene expression at the transcriptional level. The molecular mechanism of insulin action is mediated via interaction of the functional IRE upstream of the ACAT1 P1 promoter with C/EBPα and is MAPK-dependent. J. Cell. Biochem. 114: 2188–2198, 2013. © 2013 Wiley Periodicals, Inc.