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

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 (#UMI08686). 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.