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Am J Physiol Gastrointest Liver Physiol. 2015 Jul 1;309(1):G42-51. doi: 10.1152/ajpgi.00443.2014. Epub 2015 May 21.

The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.

Author information

1
Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan;
2
Division of Diabetes and Metabolism, Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan;
3
Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; and.
4
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
5
Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima, Japan; tasano@hiroshima-u.ac.jp.

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.

KEYWORDS:

febuxostat; hyperuricemia; nonalcoholic steatohepatitis; uric acid; xanthine oxidase inhibitor

PMID:
25999428
DOI:
10.1152/ajpgi.00443.2014
[Indexed for MEDLINE]
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