Uric Acid Metabolism in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver pathology characterised by excessive fat accumulation in hepatocytes in the absence of significant alcohol intake. Uric acid, the end product of purine catabolism, has emerged as both a biomarker and a potential mediator of hepatic lipid accumulation. Elevated uric acid levels can arise from enhanced fructose metabolism or impaired renal excretion and may induce mitochondrial oxidative stress, inhibit key tricarboxylic acid cycle enzymes and promote de novo lipogenesis. These effects amplify insulin resistance, lipid peroxidation and inflammatory signalling within the liver. Epidemiological studies have established positive correlations between serum uric acid and the prevalence, severity and progression of NAFLD across diverse populations. At a mechanistic level, uric acid fosters an environment conducive to steatosis through activation of xanthine oxidase–derived reactive oxygen species and downstream inflammatory pathways. Clinically, these insights underpin interest in non-invasive markers of disease activity and in repurposing urate-lowering agents to mitigate hepatic steatosis. Given the global rise of metabolic syndrome, understanding uric acid metabolism in NAFLD holds considerable significance for early detection, risk stratification and development of targeted therapies.

Research from Nature Portfolio

Recent work has investigated the prognostic value of serum uric acid in patients with steatosis but preserved renal function, demonstrating that uric acid alone does not independently predict long-term mortality when adjusted for age, sex and comorbidities. In parallel, experimental and clinical studies of xanthine oxidase inhibition have revealed that febuxostat, more so than allopurinol, reduces hepatic xanthine oxidase activity, uric acid accumulation and oxidative stress in a diet-induced steatohepatitis model. An accompanying open-label intervention in individuals with hyperuricaemia showed that febuxostat treatment over several months lowered serum transaminases and markers of inflammation, highlighting xanthine oxidase as a promising therapeutic target in NAFLD and its inflammatory sequelae.

Uric Acid Metabolism in Nonalcoholic Fatty Liver Disease publication trend

The graph below shows the total number of articles in uric acid metabolism in nonalcoholic fatty liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Nonalcoholic fatty liver disease (NAFLD): A spectrum of liver conditions marked by excessive triglyceride accumulation in hepatocytes, unrelated to alcohol consumption.

Uric acid: The final oxidation product of purine metabolism in humans, primarily excreted by the kidneys.

Hyperuricaemia: A condition of elevated blood uric acid levels, often defined as >360 μmol/L in women and >420 μmol/L in men.

Xanthine oxidase (XO): A hepatic enzyme that catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid, generating reactive oxygen species.

Controlled attenuation parameter (CAP): A non-invasive ultrasound-based metric for quantifying hepatic steatosis by measuring sound attenuation through fatty liver.

De novo lipogenesis: The metabolic pathway by which acetyl-CoA is converted into fatty acids in the liver, contributing to triglyceride synthesis.

References

1. Hyperuricemia as an effect modifier of the association between metabolic phenotypes and nonalcoholic fatty liver disease in Chinese population. Journal of Translational Medicine (2023).
2. Association of serum uric acid with hepatic steatosis detected by controlled attenuation parameter in the United States population. Lipids in Health and Disease (2023).
3. Allopurinol versus Febuxostat: A New Approach for the Management of Hepatic Steatosis in Metabolic Dysfunction-Associated Steatotic Liver Disease. Biomedicines (2023).
4. Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress POTENTIAL ROLE IN FRUCTOSE-DEPENDENT AND -INDEPENDENT FATTY LIVER*. Journal of Biological Chemistry (2012).
5. Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice. Scientific Reports (2020).
6. Serum uric acid levels and prognosis of patients with non-alcoholic fatty liver disease. Scientific Reports (2024).