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Xanthine Oxidase Inhibition Attenuates Insulin Resistance and Diet-Induced Steatohepatitis in Mice

29 Pages Posted: 22 May 2019

See all articles by Tomoki Nishikawa

Tomoki Nishikawa

Kanazawa University - Graduate School of Medical Sciences

Naoto Nagata

Kanazawa University - Department of Cell Metabolism and Nutrition; Kanazawa University - Graduate School of Medical Sciences

Tetsuro Shimakami

Kanazawa University - Department of Gastroenterology

Takashi Shirakura

Teijin Pharma Limited

Chieko Matsui

Teijin Pharma Limited

Yinhua Ni

Kanazawa University - Department of Cell Metabolism and Nutrition

Fen Zhuge

Kanazawa University - Department of Cell Metabolism and Nutrition

Liang Xu

Kanazawa University - Department of Cell Metabolism and Nutrition

Guanliang Chen

Kanazawa University - Department of Cell Metabolism and Nutrition

Mayumi Nagashimada

Kanazawa University - Department of Cell Metabolism and Nutrition

Taro Yamashita

Kanazawa University - Department of Gastroenterology

Yoshio Sakai

Kanazawa University - Department of Gastroenterology

Tatsuya Yamashita

Kanazawa University - Department of Gastroenterology; Kanazawa University - Department of Cell Metabolism and Nutrition

Eishiro Mizukoshi

Kanazawa University - Graduate School of Medical Sciences

Masao Honda

Kanazawa University - Graduate School of Medical Sciences

Shuichi Kaneko

Kanazawa University - Department of Gastroenterology

Tsuguhito Ota

Asahikawa Medical University, Department of Medicine, Division of Metabolism and Biosystemic Science; Kanazawa University - Department of Cell Metabolism and Nutrition

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Abstract

Background: Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO could improve nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis.

Methods: To investigate the effects of febuxostat and allopurinol, XO inhibitors clinically used for gout, on diet-induced NASH, C57BL/6J mice were fed a high-fat, high-cholesterol, and cholate diet (CL diet) with or without either 0.001% febuxostat or 0.003% allopurinol for 18 weeks. Systemic glucose tolerance and insulin sensitivity, liver histology, inflammation, and oxidative stress were tested. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia.

Findings: Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic UA levels in CL diet-fed mice. This reduction in hepatic UA levels was accompanied by alleviated insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by a reduction in serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase.

Interpretation: XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.

Trial Registration: The study has been registered with UMIN-CTR (#UMIN000008686).

Funding Statement: This work was supported by Grants-in-aid for Scientific Research (B) (25282017) and Challenging Exploratory Research (15K12698) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Japan Diabetes Foundation (to T.O.). This study was also supported by Teijin Pharma Limited.

Declaration of Interests: The authors declare no conflict of interest associated with this manuscript.

Ethics Approval Statement: The study was approved by the Ethics Committee of Kanazawa University Hospital. All animal procedures were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of Kanazawa University, Japan.

Keywords: uric acid, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, xanthine oxidase, oxidative stress, inflammation

Suggested Citation

Nishikawa, Tomoki and Nagata, Naoto and Shimakami, Tetsuro and Shirakura, Takashi and Matsui, Chieko and Ni, Yinhua and Zhuge, Fen and Xu, Liang and Chen, Guanliang and Nagashimada, Mayumi and Yamashita, Taro and Sakai, Yoshio and Yamashita, Tatsuya and Mizukoshi, Eishiro and Honda, Masao and Kaneko, Shuichi and Ota, Tsuguhito, Xanthine Oxidase Inhibition Attenuates Insulin Resistance and Diet-Induced Steatohepatitis in Mice (May 19, 2019). Available at SSRN: https://ssrn.com/abstract=3391355

Tomoki Nishikawa

Kanazawa University - Graduate School of Medical Sciences

Kanazawa
Japan

Naoto Nagata

Kanazawa University - Department of Cell Metabolism and Nutrition

Japan

Kanazawa University - Graduate School of Medical Sciences

Kanazawa
Japan

Tetsuro Shimakami

Kanazawa University - Department of Gastroenterology

Kanazawa
Japan

Takashi Shirakura

Teijin Pharma Limited

Japan

Chieko Matsui

Teijin Pharma Limited

Japan

Yinhua Ni

Kanazawa University - Department of Cell Metabolism and Nutrition

Japan

Fen Zhuge

Kanazawa University - Department of Cell Metabolism and Nutrition

Japan

Liang Xu

Kanazawa University - Department of Cell Metabolism and Nutrition

Japan

Guanliang Chen

Kanazawa University - Department of Cell Metabolism and Nutrition

Japan

Mayumi Nagashimada

Kanazawa University - Department of Cell Metabolism and Nutrition

Japan

Taro Yamashita

Kanazawa University - Department of Gastroenterology

Kanazawa
Japan

Yoshio Sakai

Kanazawa University - Department of Gastroenterology

Kanazawa
Japan

Tatsuya Yamashita

Kanazawa University - Department of Gastroenterology

Kanazawa
Japan

Kanazawa University - Department of Cell Metabolism and Nutrition

Japan

Eishiro Mizukoshi

Kanazawa University - Graduate School of Medical Sciences

Kanazawa
Japan

Masao Honda

Kanazawa University - Graduate School of Medical Sciences

Kanazawa
Japan

Shuichi Kaneko

Kanazawa University - Department of Gastroenterology

Kanazawa
Japan

Tsuguhito Ota (Contact Author)

Asahikawa Medical University, Department of Medicine, Division of Metabolism and Biosystemic Science ( email )

Japan

Kanazawa University - Department of Cell Metabolism and Nutrition ( email )

Japan

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