Journal
WORLD JOURNAL OF GASTROENTEROLOGY
Volume 13, Issue 42, Pages 5635-5641Publisher
W J G PRESS
DOI: 10.3748/wjg.v13.i42.5635
Keywords
apoptosis; CYP4A; fatty acid oxidation; inflammation
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Funding
- NIDDK NIH HHS [R37 DK041876, DK41876, T32 DK007198, R01 DK041876, T32 DK07198-26] Funding Source: Medline
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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 omega-oxidation and peroxisomal beta-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. (c) 2007 WJG. All rights reserved.
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