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Pitavastatin ameliorates severe hepatic steatosis in aromatase‐deficient (Ar−/−) mice
Author(s) -
Egawa Tetsu,
Toda Katsumi,
Nemoto Yoshihisa,
Ono Masafumi,
Akisawa Naoaki,
Saibara Toshiji,
Hayashi Yoshihiro,
Hiroi Makoto,
Enzan Hideaki,
Onishi Saburo
Publication year - 2003
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-003-1093-x
Subject(s) - steatosis , aromatase , endocrinology , medicine , nonalcoholic fatty liver disease , pitavastatin , beta oxidation , estrogen receptor , steatohepatitis , tamoxifen , chemistry , biology , fatty liver , statin , breast cancer , cancer , metabolism , disease
Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA β‐oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA β‐oxidation by administering a novel statin, pitavastatin, to aromatase‐deficient (Ar−/−) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar−/− mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA β‐oxidation such as very long fatty acyl‐CoA synthetase in peroxisome, peroxisomal fatty acyl‐CoA oxidase, and medium‐chain acyl‐CoA dehydrogenase. Severe hepatic steatosis observed in Ar−/− mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA β‐oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA β‐oxidation in vivo via the peroxisome proliferator‐activated receptor‐α‐mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.