Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice

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. Nonalcoholic fatty liver disease (NAFLD), one of the most common liver diseases worldwide 1 , is strongly associated with insulin resistance and features of metabolic syndrome such as obesity, hyperlipidemia, and type 2 diabetes 1,2. NAFLD ranges from simple steatosis to more advanced nonalcoholic steatohepatitis (NASH) characterized by steatosis in combination with inflammation and fibrosis 3,4. Besides insulin resistance, increased inflammatory cytokines, reactive oxygen species (ROS), and subsequent lipid peroxidation are thought to drive the progression of NASH, leading to liver cirrhosis and hepatocellular carcinoma 3,5. Thus, in addition to conventional approaches based on of diet-and exercise-related adjunct therapies, an effective therapeutic approach is urgently needed for NASH. Besides metabolic syndrome-related conditions, hyperuricemia, characterized by high serum uric acid (UA) levels, has also been linked to NAFLD. Several epidemiological studies have demonstrated that patients with NAFLD have significantly higher serum UA levels relative to controls, and elevated serum UA levels are an independent risk factor for NAFLD 6-8. Notably, 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

Decrease in Serum Urate Level Is Associated With Loss of Visceral Fat in Male Gout Patients

“…Elevated insulin resistance was observed to be associated with greater loss of lean body mass ( 43 ). In addition, both clinical and experimental improvements in insulin resistance are aligned with decrease in SU level ( 44 – 46 ). These associations lead us to speculate that improved insulin resistance might play a role in skeletal muscle mass gain in gout patients undergoing ULT.…”

Influence of cardiometabolic comorbidities on myocardial function, infarction, and cardioprotection: Role of cardiac redox signaling

“…Enhanced p66 shc signaling, increased opening probability of the mPTP and higher levels of mitochondrial damage-associated molecular patterns (DAMPs) were reported for rodent models of NASH [366][367][368] that may explain the increased mitochondrial ROS formation. XO inhibition could efficiently prevent the major pathophysiological changes in rodent models of NASH [369,370]. Finally, neuroinflammatory processes through the liver-brain-axis may come into play, again involving ROS formation (e.g.…”

Treatment of Fatty Liver Disease: The Present and the Future

“…Febuxostat: Febuxostat is a xanthine oxidase inhibitor that has been shown to slow the progression of NAFLD/NASH. Nishikawa et al conducted a study to test the efficacy of febuxostat in mice with NASH which was then followed by a single-arm, open-label trial of febuxostat in patients with NASH who also have hyperuricemia [ 23 ].…”

“…Mice were fed a high-fat diet, febuxostat was shown to decrease the xanthine oxidase level in the hepatocytes of these mice, lower insulin resistance, improve glucose tolerance, prevent lipid accumulation and steatosis, protect against hepatic fibrosis. The hepatic damage due to inflammation and oxidative stress was also lower in mice treated with febuxostat [ 23 ].…”

“…In patients who had a moderate liver injury the liver enzymes like AST, ALT was lowered following treatment with febuxostat. Liver biopsies of these patients showed a significant improvement in steatosis but no change in the inflammation or ballooning degeneration [ 23 ].…”