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- Title
Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration
- Authors
Yoshikawa, Takashi; Toda, Katsumi; Nemoto, Yoshihisa; Ono, Masafumi; Iwasaki, Shinji; Maeda, Takashi; Saibara, Toshiji; Hayashi, Yoshihiro; Miyazaki, Eriko; Hiroi, Makoto; Enzan, Hideaki; Shizuta, Yutaka; Onishi, Saburo
- Abstract
Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Recently, aromatase-deficient (ArKO, Ar−/−) mice lacking intrinsic estrogen was developed and the molecular mechanism involved in progression of massive hepatic steatosis in estrogen-deficiency was elucidated; impairment in hepatic fatty acid β-oxidation of peroxisomes, microsomes and mitochondria. This impairment is latent, but is potentially serious, because hepatic energy supply depends greatly on fatty acid β-oxidation. Therefore in the present study, we tried to conquer impaired hepatic fatty acid β-oxidation by administrating bezafibrate, a potent peroxisome proliferator, to Ar−/− mice through activating fatty acid β-oxidation via the peroxisome proliferator activated receptor-α mediated signaling pathway. Northern blot analysis of Ar−/− mice liver revealed a significant restoration of mRNA expression of very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase in mitochondria, essential enzymes in fatty acid β-oxidation by administration of bezafibrate. Severe hepatic steatosis observed in Ar−/− mice regressed dramatically. Consistent findings were obtained in the in vitro assays of fatty acid β-oxidation activity. These findings demonstrate that bezafibrate is capable of restoring impaired fatty acid β-oxidation in vivo via the peroxisome proliferator-activated receptor-α mediated signaling pathway and is potent enough to regress severe hepatic steatosis in mice deficient in intrinsic estrogen.
- Subjects
FATTY degeneration; DEGENERATION (Pathology); THERAPEUTICS
- Publication
Hepatology Research, 2002, Vol 22, Issue 4, p278
- ISSN
1386-6346
- Publication type
Article
- DOI
10.1016/S1386-6346(01)00145-0