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The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.
Am J Physiol Gastrointest Liver Physiol. 2015 Jul 01; 309(1):G42-51.AJ

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+Show Affiliations

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

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

25999428

Citation

Nakatsu, Yusuke, et al. "The Xanthine Oxidase Inhibitor Febuxostat Suppresses Development of Nonalcoholic Steatohepatitis in a Rodent Model." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 309, no. 1, 2015, pp. G42-51.
Nakatsu Y, Seno Y, Kushiyama A, et al. The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model. Am J Physiol Gastrointest Liver Physiol. 2015;309(1):G42-51.
Nakatsu, Y., Seno, Y., Kushiyama, A., Sakoda, H., Fujishiro, M., Katasako, A., Mori, K., Matsunaga, Y., Fukushima, T., Kanaoka, R., Yamamotoya, T., Kamata, H., & Asano, T. (2015). The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model. American Journal of Physiology. Gastrointestinal and Liver Physiology, 309(1), G42-51. https://doi.org/10.1152/ajpgi.00443.2014
Nakatsu Y, et al. The Xanthine Oxidase Inhibitor Febuxostat Suppresses Development of Nonalcoholic Steatohepatitis in a Rodent Model. Am J Physiol Gastrointest Liver Physiol. 2015 Jul 1;309(1):G42-51. PubMed PMID: 25999428.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model. AU - Nakatsu,Yusuke, AU - Seno,Yasuyuki, AU - Kushiyama,Akifumi, AU - Sakoda,Hideyuki, AU - Fujishiro,Midori, AU - Katasako,Aya, AU - Mori,Keiichi, AU - Matsunaga,Yasuka, AU - Fukushima,Toshiaki, AU - Kanaoka,Ryuhei, AU - Yamamotoya,Takeshi, AU - Kamata,Hideaki, AU - Asano,Tomoichiro, Y1 - 2015/05/21/ PY - 2014/12/15/received PY - 2015/04/30/accepted PY - 2015/5/23/entrez PY - 2015/5/23/pubmed PY - 2015/9/15/medline KW - febuxostat KW - hyperuricemia KW - nonalcoholic steatohepatitis KW - uric acid KW - xanthine oxidase inhibitor SP - G42 EP - 51 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am. J. Physiol. Gastrointest. Liver Physiol. VL - 309 IS - 1 N2 - 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. SN - 1522-1547 UR - https://www.unboundmedicine.com/medline/citation/25999428/The_xanthine_oxidase_inhibitor_febuxostat_suppresses_development_of_nonalcoholic_steatohepatitis_in_a_rodent_model_ L2 - http://www.physiology.org/doi/full/10.1152/ajpgi.00443.2014?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -