摘要
Non-alcoholic fatty liver disease(NAFLD)is a hepatic metabolic syndrome arisingfrom lipid metabolic imbalance,with its prevalence increasing globally.In this study,weobserved a significant up-regulation of interferon regulatory factor 8(IRF8)in the liver ofNAFLD model mice and patients.Overexpression of IRF8 induced lipid accumulation in themouse primary hepatocytes.Mice with adeno-associated virus-mediated IRF8 overexpressionexhibited hepatic steatosis due to up-regulated peroxisome proliferator-activated receptorγ(PPARγ)expression and increased fatty acid uptake and lipogenesis.In vitro,small interfering RNA-mediated IRF8 knockdown attenuated triglyceride accumulation by dampening PPARγexpression through transcriptional inhibition of brain and muscle ARNT-like 1.ThePPARγ-specific antagonist GW9662 abolished the effect of IRF8 overexpression.Furthermore,adeno-associated virus-mediated IRF8 knockdown in the mouse liver markedly alleviated hepatic steatosis and obesity-related metabolic syndrome.These findings indicate that IRF8 playsa vital role in modulating hepatic lipid metabolism in a PPARγ-dependent manner and providea previously unknown insight into NAFLD therapeutic strategies.
基金
supported by grants from the National Science Foundation of China(No.81974118,82325010)
The Shanghai Outstanding Academic Leaders(China)(No.20XD1433300)
the Shuguang Project of China(21SG11)
the Innovative Research Team of High-level Local Universities in Shanghai,China(No.SHSMU-ZDCX20212700)
the Major Natural Science Project of the Scientific Research and Innovation Plan of Shanghai Municipal Commission of Education(China)(No.2023ZKZD17)
the Shanghai Research Center for Endocrine and Metabolic Diseases(China)(No.2022ZZ01002)
the Shanghai Sixth People’s Hospital Foundation(China)(No.ynqn202105).
