High Uric Acid Induces Liver Fat Accumulation Via ROS/JNK/AP-1 Signaling

Uric acid(UA)is the end product of purine metabolism.Normally,internal UA is in a state of dynamic equilibrium.However,hyperuricemia(HUA)occurs when excessive intake of high-purine foods,or abnormal uric acid excretion.Recently,increasing studies have shown the association between SUA level and NAFLD.Despite the identifying molecular link between HUA and NAFLD,the underlying mechanism is still unclear.The mitogen-activated protein kinases(MAPKs)consist of c-Jun N-terminal kinase(JNK),p38 MAPK and extracellular signal-regulated kinase(ERK).JNK plays a prominent role in liver glucose and lipid metabolism.Previously,we reported that HUA induced aberrant activation of JNK,p38 and ERK and excessive intracellular ROS production in vitro.In this study,we established hyperuricemia mouse model through uric oxidase-knockout(Uox-KO)to investigate the role of HUA in the progression of hepatic fat accumulation.Uox-KO mice showed the higher levels of serum UA,FBG,TC,ALT and liver TG,TC.In order to explore the specific mechanism,we detected the phosphorylation expression of MAPKs.We found that HUA activated the p38 and JNK signaling pathways in vivo and in vitro.In addition,JNK inhibitor SP600125 ameliorated uric acid-mediated hepatic fat accumulation in vivo and in vitro by regulating transcription activity of FAS via transcription factor AP-1.In addition,UA promoted intracellular ROS accumulation,which mediated JNK phosphorylation and lipid accumulation.In summary,we found that uric acid induces liver fat accumulation through the ROS/JNK/AP-1 pathway.This evidence suggests a new mechanism for the pathogenesis of NAFLD and a new treatment strategy for hyperuricemia-induced NAFLD.