Abstract

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 improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of 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 reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.

Highlights

  • Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD)

  • To determine the effect of xanthine oxidase (XO) inhibitors on diet-induced nonalcoholic steatohepatitis (NASH), C57BL/6J mice were split into four groups and fed NC, the cholate diet (CL diet), or the CL diet supplemented with either 0.001% (w/w) febuxostat (CL + Feb) or 0.003% (w/w) allopurinol (CL + Allo) for 18 weeks

  • We demonstrated that both febuxostat and allopurinol alleviated glucose intolerance, hepatic steatosis and fibrosis, in mice fed the CL diet

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Summary

Introduction

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. UA itself has been reported to promote de novo lipogenesis and induce insulin resistance, both in vivo and in vitro, through increased NADPH oxidase (NOX)-mediated ROS generation[9,10] and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome[11] These observations indicate that hyperuricemia plays a causative role in the development of NAFLD; it is not merely a consequence of this liver disease. A previous study demonstrated that the expression and activity of hepatic XO are significantly increased in high-fat diet-induced obese mice, while allopurinol, a classical XO inhibitor with a purine-like structure, improves insulin resistance and hepatic steatosis in these mice[11] It remains unclear whether and how lowering UA by inhibiting XO improves NASH, which is characterized by more advanced liver inflammation and fibrosis. We conducted a pilot intervention study with febuxostat for NAFLD patients with hyperuricemia

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