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World J Gastroenterol. Nov 14, 2007; 13(42): 5635-5641
Published online Nov 14, 2007. doi: 10.3748/wjg.v13.i42.5635
Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse
Edwina S Baskin-Bey, Akira Anan, Hajime Isomoto, Steven F Bronk, Gregory J Gores
Edwina S Baskin-Bey, Akira Anan, Hajime Isomoto, Steven F Bronk, Gregory J Gores, Department of Medicine, Division of Gastroenterology and Hepatology, Miles and Shirely Fitterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
Author contributions: All authors contributed equally to the work.
Supported by NIH grants T32 DK07198-26 (to ESB) and DK41876 (to GJG), and the Palumbo and Mayo Foundation
Correspondence to: Gregory J Gores, MD, Professor of Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, United States. gores.gregory@mayo.edu
Telephone: +1-507-2840686 Fax: +1-507-2840762
Received: June 15, 2007
Revised: August 10, 2007
Accepted: October 8, 2007
Published online: November 14, 2007
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.

Keywords: Apoptosis; CYP4A; Fatty acid oxidation; Inflammation