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Yoshikawa T, Toda K, Nemoto Y, et al. Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration. Hepatol Res. 2002;22(4):278-287doi: 10.1016/s1386-6346(01)00145-0.
Yoshikawa, T., Toda, K., Nemoto, Y., Ono, M., Iwasaki, S., Maeda, T., Saibara, T., Hayashi, Y., Miyazaki, E., Hiroi, M., Enzan, H., Shizuta, Y., & Onishi, S. (2002). Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration. Hepatology research : the official journal of the Japan Society of Hepatology, 22(4), 278-287. https://doi.org/10.1016/s1386-6346(01)00145-0
Yoshikawa, Takashi, et al. "Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration." Hepatology research : the official journal of the Japan Society of Hepatology vol. 22,4 (2002): 278-287. doi: https://doi.org/10.1016/s1386-6346(01)00145-0
Yoshikawa T, Toda K, Nemoto Y, Ono M, Iwasaki S, Maeda T, Saibara T, Hayashi Y, Miyazaki E, Hiroi M, Enzan H, Shizuta Y, Onishi S. Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration. Hepatol Res. 2002 Apr;22(4):278-287. doi: 10.1016/s1386-6346(01)00145-0. PMID: 11929713.
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Hepatol Res. 2002 Apr;22(4):278-287. doi: 10.1016/s1386-6346(01)00145-0.

Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration.

Hepatology research : the official journal of the Japan Society of Hepatology

Takashi Yoshikawa, Katsumi Toda, Yoshihisa Nemoto, Masafumi Ono, Shinji Iwasaki, Takashi Maeda, Toshiji Saibara, Yoshihiro Hayashi, Eriko Miyazaki, Makoto Hiroi, Hideaki Enzan, Yutaka Shizuta, Saburo Onishi

Affiliations

  1. Department of Medicine, Kochi Medical School, 783-8505, Nankoku, Japan

PMID: 11929713 DOI: 10.1016/s1386-6346(01)00145-0

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 beta-oxidation of peroxisomes, microsomes and mitochondria. This impairment is latent, but is potentially serious, because hepatic energy supply depends greatly on fatty acid beta-oxidation. Therefore in the present study, we tried to conquer impaired hepatic fatty acid beta-oxidation by administrating bezafibrate, a potent peroxisome proliferator, to Ar-/- mice through activating fatty acid beta-oxidation via the peroxisome proliferator activated receptor-alpha 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 beta-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 beta-oxidation activity. These findings demonstrate that bezafibrate is capable of restoring impaired fatty acid beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha mediated signaling pathway and is potent enough to regress severe hepatic steatosis in mice deficient in intrinsic estrogen.

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