Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse

Edwin S. Baskin-Rey, Akira Anan, Hajime Isomoto, Steven F. Bronk, Gregory J. Gores

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Aim: To ascertain whether constitutive androstane receptor (CAR) activation by 1,4-bis-[2-(3,5,-dichloropyridyloxy)] benzene (TCPOBOP) modulates steatohepatitis in the methionine choline-deficient (MCD) diet-fed animal. Methods: C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol. Results: Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis (44.6 ± 5.4% vs 30.4 ± 4.5%, P < 0.05) and serum triglyceride levels (48 ± 8 vs 20 ± 1 mg/dL, P < 0.05) in MCD diet-fed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal ω-oxidation and peroxisomal β-oxidation, namely CYP4A10, LPBE, and 3-ketoacyl-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters. Conclusion: CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.

Original languageEnglish (US)
Pages (from-to)5635-5641
Number of pages7
JournalWorld journal of gastroenterology
Volume13
Issue number42
DOIs
StatePublished - Nov 14 2007

Keywords

  • Apoptosis
  • CYP44
  • Fatty acid oxidation
  • Inflammation

ASJC Scopus subject areas

  • Gastroenterology

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