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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.
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 the CAR agonist, TCPOBOP, or the CAR inverse agonist, and orrostanol.RESULTS: Expression of CYP2B10 and CYP3A11, known CAR target genes, increased by 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. CPOBOP treatment reduced hepatic steatosis (44.6 ± 5.4% vs 30.4 ± 4.5%, P <0.05) and serum triglyceride levels 20 ± 1 mg / dL, P <0.05) in MCD diet-fed mice as compared with the standard diet-fed mice. His 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. reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. Contrast, and rostanol 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.