PPARalpha ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats.
Oxidative stress is a major pathogenetic factor in hepatic fibrosis. Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor which is known to affect oxidative stress and PPARalpha ligands may have rescue effects on hepatic fibrosis. We tested this hypothesis using rat thioacetamide (TAA) models of liver cirrhosis. Rats were given intraperitoneal injection of TAA and treated with a diet containing one of the two PPARalpha ligands, Wy-14,643 (WY) or fenofibrate. WY treatment dramatically reduced hepatic fibrosis and also prevented the inhibition catalase of mRNA expression caused by TAA. Correspondingly, catalase activity increased in the TAA+WY group but decreased in the control TAA group. The antifibrotic action of fenofibrate in the TAA model was comparable with that of WY. PPARalpha ligands have an antifibrotic action in the rat TAA model of liver cirrhosis, probably due to an antioxidant effect of enhanced catalase expression and activity in the liver.
Toyama
Tetsuya
T
Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
Nakamura
Hideki
H
Harano
Yuichi
Y
Yamauchi
Norihito
N
Morita
Atsuhiro
A
Kirishima
Toshihiko
T
Minami
Masahito
M
Itoh
Yoshito
Y
Okanoue
Takeshi
T
D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D015152:Blotting, Northern; D002374:Catalase / Q000378:metabolism; D003720:Densitometry; D011345:Fenofibrate / Q000494:pharmacology; D005355:Fibrosis / Q000473:pathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis; D008297:Male; D008954:Models, Biological; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D013853:Thioacetamide / Q000494:pharmacology
D000975:Antioxidants; D008024:Ligands; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D013853:Thioacetamide; C006253:pirinixic acid; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D011345:Fenofibrate