Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism

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• 作者：Xingyong Wan^&dagger ; ; Chengfu Xu^&dagger ; ; Yiming Lin ; Chao Lu ; Dejian Li ; Jianzhong Sang ; Haijian He ; Xiao Liu ; Youming Li ; ^{xiaofu@zju.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Chaohui Yu ; ^{ych623@sina.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：DMEM ; Dulbecco&rsquo ; s modified eagle medium ; FFA ; free fatty acids ; HFD ; high fat diet ; HUA ; hyperuricemia-inducing diet ; HF-HUA ; high fat diet combined with hyperuricemia-inducing diet ; H&E ; hematoxylin-eosin ; ITT ; insulin tolerance test ; GTT ; glucose tolerance test ; MS ; metabolic syndrome ; NAFLD ; nonalcoholic fatty liver disease ; NLRP3 ; NOD-like receptor family pyrin domain containing 3 ; siRNA ; small interfering RNA ; SCD ; standard chow diet
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：64
• 期：4
• 页码：925-932
• 全文大小：3185 K

文摘

Hyperuricemia significantly increases risk of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. However, the mechanisms responsible for this association are as yet unclear. This study aimed to investigate the effects and underlying mechanisms of uric acid on development of NAFLD and insulin resistance.

Methods

We initially analyzed the impact of uric acid on the development of hepatic steatosis and insulin resistance in mice and in two cell models, HepG2 and L02. Subsequently, we studied the role of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in uric acid-induced fat accumulation and insulin signaling impairment.

Results

We found that uric acid directly induces hepatocyte fat accumulation, insulin resistance, and insulin signaling impairment both in vivo and in vitro. We also found that uric acid-induced NLRP3 inflammasome activation, whereas lowering uric acid by allopurinol inhibited NLRP3 inflammasome activation in a high fat diet mouse model of NAFLD. Moreover, knocking down NLRP3 expression significantly attenuated uric acid-induced fat accumulation both in HepG2 cells and L02 cells. Knocking down NLRP3 expression also rescued uric acid-induced insulin signaling impairment in both cell types.

Conclusions

Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome. Uric acid may be a new therapeutic target for NAFLD and insulin resistance.