Title: Heat shock factor-1 knockout enhances cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter (MDR1) gene expressions to attenuate atherosclerosis.
Authors: Krishnamurthy, Karthikeyan; Glaser, Shannon; Alpini, Gianfranco D; Cardounel, Arturo J; Liu, Zhenguo; Ilangovan, Govindasamy
Published In Cardiovasc Res, (2016 07 01)
Abstract: Stress response, in terms of activation of stress factors, is known to cause obesity and coronary heart disease such as atherosclerosis in human. However, the underlying mechanism(s) of these pathways are not known. Here, we investigated the effect of heat shock factor-1 (HSF-1) on atherosclerosis.HSF-1 and low-density lipoprotein receptor (LDLr) double knockout (HSF-1(-/-)/LDLr(-/-)) and LDLr knockout (LDLr(-/-)) mice were fed with atherogenic western diet (WD) for 12 weeks. WD-induced weight gain and atherosclerotic lesion in aortic arch and carotid regions were reduced in HSF-1(-/-)/LDLr(-/-) mice, compared with LDLr(-/-) mice. Also, repression of PPAR-γ2 and AMPKα expression in adipose tissue, low hepatic steatosis, and lessened plasma adiponectins and lipoproteins were observed. In HSF-1(-/-)/LDLr(-/-) liver, higher cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter [MDR1/P-glycoprotein (P-gp)] gene expressions were observed, consistent with higher bile acid transport and larger hepatic bile ducts. Luciferase reporter gene assays with wild-type CYP7A1 and MDR1 promoters showed lesser luminescence than with mutant promoters (HSF-1 binding site deleted), indicating that HSF-1 binding is repressive of CYP7A1 and MDR1 gene expressions.HSF-1 ablation not only eliminates heat shock response, but it also transcriptionally up-regulates CYP7A1 and MDR1/P-gp axis in WD-diet fed HSF-1(-/-)/LDLr(-/-) mice to reduce atherosclerosis.
PubMed ID: 27131506
MeSH Terms: AMP-Activated Protein Kinases/metabolism; ATP Binding Cassette Transporter, Subfamily B/genetics; ATP Binding Cassette Transporter, Subfamily B/metabolism*; Adipose Tissue/enzymology; Animals; Aorta/metabolism; Aorta/pathology; Aortic Diseases/enzymology; Aortic Diseases/genetics; Aortic Diseases/pathology; Aortic Diseases/prevention & control*; Atherosclerosis/enzymology; Atherosclerosis/genetics; Atherosclerosis/pathology; Atherosclerosis/prevention & control*; Binding Sites; Carotid Arteries/metabolism; Carotid Arteries/pathology; Carotid Artery Diseases/enzymology; Carotid Artery Diseases/genetics; Carotid Artery Diseases/pathology; Carotid Artery Diseases/prevention & control*; Cells, Cultured; Cholesterol 7-alpha-Hydroxylase/genetics; Cholesterol 7-alpha-Hydroxylase/metabolism*; DNA-Binding Proteins/deficiency*; DNA-Binding Proteins/genetics; Diet, Western; Disease Models, Animal; Female; Genetic Predisposition to Disease; Heat Shock Transcription Factors; Liver/enzymology*; Male; Mice, Inbred C57BL; Mice, Knockout; Mutation; PPAR gamma/metabolism; Phenotype; Plaque, Atherosclerotic; Promoter Regions, Genetic; Receptors, LDL/deficiency; Receptors, LDL/genetics; Signal Transduction; Time Factors; Transcription Factors/deficiency*; Transcription Factors/genetics; Transcription, Genetic; Transfection; Up-Regulation