Abstract
Uric acid is the end metabolite derived from the oxidation of purine compounds. Overwhelming evidence shows the vital interrelation between hyperuricemia (HUA) and non-alcoholic fatty liver disease (NAFLD). However, the mechanisms for this association remain unclear. In this study, we investigated the effect of HUA on fat accumulation in human HepG2 hepatoma cells and urate oxidase-knockout (Uox-KO) mice. HUA activated c-Jun N-terminal kinase (JNK) in vivo and in vitro. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased fat accumulation and lipogenic gene expression induced by HUA. Overexpression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase 1 was via activation of JNK, which was blocked by the JNK inhibitor SP600125. HUA activated AP-1 to upregulate lipogenic gene expression via JNK activation. In addition, HUA caused mitochondrial dysfunction and reactive oxygen species production. Pre-treatment with the antioxidant N-acetyl-L-cysteine could ameliorate HUA-activated JNK and hepatic steatosis. These data suggest that ROS/JNK/AP-1 signaling plays an important role in HUA-mediated fat accumulation in liver.
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