Journal
HEPATOLOGY RESEARCH
Volume 22, Issue 4, Pages 278-287Publisher
WILEY
DOI: 10.1016/S1386-6346(01)00145-0
Keywords
fatty liver; estrogen; peroxisome proliferator; peroxisome proliferator activated receptor-alpha mitochondria
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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. (C) 2002 Elsevier Science B.V. All rights reserved.
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