Sterol 27-hydroxylase gene dosage and the antiatherosclerotic effect of Rifampicin in mice

Biosci Rep. 2018 Jan 25;38(1):BSR20171162. doi: 10.1042/BSR20171162. Print 2018 Feb 28.

Abstract

Sterol 27-hydroxylase (CYP27A1) catalyzes the hydroxylation of cholesterol to 27-hydroxycholesterol (27-OHC) and regulates cholesterol homeostasis. In Cyp27a1/ Apolipoprotein E (ApoE) double knockout (KO) mice fed with Western diet (WD), the atherosclerotic phenotype found in ApoE KO mice was reversed. As protective mechanism, up-regulation of Cyp3a11 and Cyp7a1 was proposed. Cyp27a1 heterozygote/ApoE KO (het) mice, with reduced Cyp27a1 expression and normal levels of Cyp7a1 and Cyp3a11, developed more severe lesions than ApoE KO mice. To analyze the contribution of Cyp3a11 to the protection of atherosclerosis development, Cyp3a11 was induced by Rifampicin (RIF) in ApoE KO and het mice. Males were fed with WD and treated daily with RIF (10 mg/kg ip) or vehicle for 4 weeks. Atherosclerosis was quantified in the aortic valve. Plasma lipids and 27-hydroxycholesterol (27-OHC), expression of cytochromes P450 and genes involved in cholesterol transport and bile acids (BAs) signaling in liver and intestine, and intestinal cholesterol absorption were analyzed. RIF increased expression of hepatic but not intestinal Cyp3a11 4-fold in both genotypes. In ApoE KO mice treated with RIF, we found a 2-fold decrease in plasma cholesterol, and a 2-fold increase in high-density lipoprotein/low-density lipoprotein ratio and CY27A1 activity. Intestinal cholesterol absorption remained unchanged and atherosclerotic lesions decreased approximately 3-fold. In het mice, RIF had no effect on plasma lipids composition, CYP27A1 activity, and atherosclerotic plaque development, despite a reduction in cholesterol absorption. In conclusion, the antiatherogenic effect of Cyp3a11 induction by RIF was also dependent on Cyp27a1 expression.

Keywords: 27-hydroxycholesterol; ApoE knock out mice; Western diet.

MeSH terms

  • Animals
  • Apolipoproteins E / genetics*
  • Atherosclerosis / drug therapy
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Cholestanetriol 26-Monooxygenase / genetics*
  • Cholesterol / genetics
  • Cholesterol / metabolism
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • Cytochrome P-450 CYP3A / genetics*
  • Diet, Western / adverse effects
  • Disease Models, Animal
  • Gene Dosage / genetics
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Knockout
  • Rifampin / administration & dosage

Substances

  • Apolipoproteins E
  • Membrane Proteins
  • Cholesterol
  • Cyp3a11 protein, mouse
  • Cytochrome P-450 CYP3A
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse
  • Cholestanetriol 26-Monooxygenase
  • Cyp27a1 protein, mouse
  • Rifampin