Dehydroepiandrosterone sulfate and cytochrome P450 inducers alleviate fatty liver in male rats fed an orotic acid-supplemented diet

Kenji Takeuchi; Hirohiko Goto; Yuko Ito; Makoto Sato; Satoshi Matsumoto; Tadashi Senba; Hideyuki Yamada; Ken Umehara

doi:10.2131/jts.40.181

Original Article

Dehydroepiandrosterone sulfate and cytochrome P450 inducers alleviate fatty liver in male rats fed an orotic acid-supplemented diet

Kenji Takeuchi, Hirohiko Goto, Yuko Ito, Makoto Sato, Satoshi Matsumoto, Tadashi Senba, Hideyuki Yamada, Ken Umehara

Author information

Kenji Takeuchi
Department of Drug Metabolism, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University
Hirohiko Goto
Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
Yuko Ito
Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
Makoto Sato
Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
Satoshi Matsumoto
Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
Tadashi Senba
Department of Toxicology, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd
Hideyuki Yamada
Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University
Ken Umehara
Department of Drug Metabolism, Drug Safety Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd

Keywords: Fatty liver, DHEAS, Phenobarbital, PPARα, Constitutive androstane receptor, Cytochrome P450

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Supplementary material

2015 Volume 40 Issue 2 Pages 181-191

DOI https://doi.org/10.2131/jts.40.181

Details

Abstract

The effects of the peroxisome proliferator, dehydroepiandrosterone sulfate (DHEAS), and the typical cytochrome P450 (CYP) inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) on fatty liver were examined in rats. Treating rats with orotic acid caused marked accumulation of lipid droplets in the liver. This effect of orotic acid was almost eradicated by co-treatment with DHEAS and PB. While DHEAS or PB alone also alleviated fatty liver, treatment with 3-MC caused little effect on a reduction in lipid droplets. Histopathological examinations revealed numerous peroxisomes in the liver of rats treated with DHEAS. In addition, a significant increase in the expression on hepatic CYPs was observed in rats the fatty liver of which was attenuated. Regarding other enzymes associated with hepatic fatty acid oxidation, the expression levels of sirtuin 1, sirtuin 6, and carnitine palmitoyltransferase 1 were also upregulated most markedly by treatment with DHEAS alone. Thus, the attenuation in fatty liver observed in the present study is likely due to peroxisome proliferation and the induction of fatty acid-metabolizing enzymes by DHEAS and typical CYP inducers.

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