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Heat shock factor-1 knockout enhances cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter (MDR1) gene

Karthikeyan Krishnamurthy1, Shannon Glaser2, Gianfranco D Alpini2

  • 1Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.

Cardiovascular Research
|May 2, 2016
PubMed
Abstract

Insights

Heat shock factor-1 (HSF-1) ablation reduces diet-induced obesity and atherosclerosis. This occurs by up-regulating cholesterol 7α-hydroxylase (CYP7A1) and MDR1/P-glycoprotein (P-gp) expression, enhancing bile acid transport.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Science

Background:

  • Stress response pathways are implicated in obesity and atherosclerosis.
  • The precise molecular mechanisms linking stress factors to these conditions remain unclear.
  • Heat shock factor-1 (HSF-1) is a key regulator of cellular stress responses.

Purpose of the Study:

  • To investigate the role of heat shock factor-1 (HSF-1) in the development of atherosclerosis.
  • To elucidate the molecular mechanisms by which HSF-1 influences metabolic and cardiovascular health.

Main Methods:

  • Utilized HSF-1 and low-density lipoprotein receptor (LDLr) double knockout mice (HSF-1(-/-)/LDLr(-/-)) and LDLr knockout mice (LDLr(-/-)).
  • Administered an atherogenic western diet (WD) for 12 weeks.
  • Analyzed weight gain, atherosclerotic lesion development, gene expression in adipose tissue and liver, plasma lipid profiles, and performed luciferase reporter gene assays.

Main Results:

  • HSF-1(-/-)/LDLr(-/-) mice exhibited reduced WD-induced weight gain and atherosclerotic lesions compared to LDLr(-/-) mice.
  • HSF-1 ablation led to repressed PPAR-γ2 and AMPKα expression, reduced hepatic steatosis, and lower plasma adiponectins and lipoproteins.
  • Increased hepatic expression of cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter MDR1/P-glycoprotein (P-gp) was observed in HSF-1(-/-)/LDLr(-/-) mice.
  • Luciferase assays indicated that HSF-1 binding represses CYP7A1 and MDR1 gene expression.

Conclusions:

  • HSF-1 ablation mitigates diet-induced obesity and atherosclerosis.
  • The absence of HSF-1 up-regulates the CYP7A1 and MDR1/P-gp axis, promoting bile acid transport and reducing atherosclerotic burden.
  • HSF-1 plays a repressive role in the regulation of CYP7A1 and MDR1/P-gp, impacting lipid metabolism and cardiovascular disease progression.
Keywords:
AtherosclerosisGlycoproteinsHeat shock factorHeat shock proteinsObesity

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