title: Insulin induces human acyl-coenzyme A: cholesterol acyltransferase1 gene expression via MAP kinases and CCAAT/enhancer-binding protein α.
abstract: 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.
authors.affiliation: Department of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ge
authors.forename: Wei
authors.initials: W
authors.lastname: Zhai
authors.forename: Bei
authors.initials: B
authors.lastname: Cheng
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Benling
authors.initials: B
authors.lastname: Qi
authors.forename: Han
authors.initials: H
authors.lastname: Lu
authors.forename: Yongli
authors.initials: Y
authors.lastname: Zeng
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D020218:Response Elements / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: ACAT; ATHEROSCLEROSIS; DIABETES; INSULIN; INSULIN RESISTANCE; INSULIN RESPONSIVE ELEMENT; SIGNAL TRANSDUCTION