Does elevated uric acid drive NAFLD and systemic vascular dysfunction?

Elevated serum uric acid (SUA) acts as both a key biomarker and a metabolic driver in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) and systemic vascular dysfunction.

Clinical and epidemiological evidence

• Independent NAFLD risk: Prospective cohorts and meta-analyses demonstrate that elevated baseline SUA is a strong, independent predictor of incident fatty liver disease. It displays a graded dose-response relationship, showing a 30% to 80% increased risk of disease onset even after adjusting for insulin resistance and metabolic syndrome.
• Causal bidirectionality: Mendelian randomization analyses support a bidirectional relationship, showing that NAFLD/MASLD causally increases SUA, while elevated uric acid genetically predisposes individuals to MASLD progression.

Mechanistic pathways

• Hepatic lipogenesis: Intracellular uric acid drives hepatic lipid accumulation by activating ROS/JNK/AP-1 and SREBP-1c pathways, which directly upregulate the key lipogenic genes ACC1 and FAS.
• Vascular oxidative stress and eNOS inhibition: Upon entering endothelial cells via urate transporters, intracellular uric acid activates NADPH oxidases and drives mitochondrial ROS production. This oxidative state initiates protein kinase C (PKC)-dependent inhibitory phosphorylation of eNOS at Thr495, reducing nitric oxide (NO) synthesis and depleting systemic NO bioavailability.

The liver–vascular feedback loop

• Systemic cardiometabolic risk: NAFLD-induced hepatic inflammation promotes the release of systemic asymmetric dimethylarginine (ADMA), an endogenous inhibitor of eNOS.
• Vicious cycle: This reduction in NO signaling impairs systemic dilation and promotes liver sinusoidal endothelial cell (LSEC) capillarization, which accelerates intrahepatic resistance, fibrosis, and coronary artery calcium (CAC) progression, ultimately increasing major adverse cardiovascular events (MACE).

Bottom line

• Elevated uric acid initiates a pathological liver–vascular feedback loop where intracellular oxidative stress, eNOS Thr495 inhibition, and hepatic lipogenesis synergistically drive NAFLD progression and cardiovascular risk.