title: The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.
abstract: Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia.
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Seno
authors.affiliation: Division of Diabetes and Metabolism, Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan;
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.affiliation: Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; and.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Aya
authors.initials: A
authors.lastname: Katasako
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Keiichi
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Yasuka
authors.initials: Y
authors.lastname: Matsunaga
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Kanaoka
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamotoya
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.affiliation: Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan; tasano@hiroshima-u.ac.jp.
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002796:Choline Deficiency / Q000150:complications; D019610:Cytoprotection; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000069465:Febuxostat; D006074:Gout Suppressants / Q000494:pharmacology*; D033461:Hyperuricemia / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D008715:Methionine / Q000172:deficiency; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013844:Thiazoles / Q000494:pharmacology*; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D013844:Thiazoles; D000069465:Febuxostat; D014527:Uric Acid; D008715:Methionine; D014969:Xanthine Oxidase
keywords: febuxostat; hyperuricemia; nonalcoholic steatohepatitis; uric acid; xanthine oxidase inhibitor