IRF8 aggravates nonalcoholic fatty liver disease via BMAL1/PPARγ axis  

作　　者：Xinyue Li Hong Zhang Fan Yu Shuting Xie Tongyu Wang Rong Zhang Guangzhong Xu Liang Wang Yeping Huang Cheng Hu 

机构地区：[1]Shanghai Diabetes Institute,Shanghai Key Laboratory of Diabetes Mellitus,Shanghai Clinical Centre for Diabetes,Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200233,China [2]Institute for Metabolic Disease,Fengxian Central Hospital Affiliated to Southern Medical University,Shanghai 201406,China [3]Surgery Centre of Diabetes Mellitus,Capital Medical University Affiliated Beijing Shijitan Hospital,Beijing 100038,China

出　　处：《Genes & Diseases》2025年第3期584-598,共15页基因与疾病(英文)

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).

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.

关 键 词：Brain and muscle ARNT-Like 1 Hepatic steatosis Interferon regulatory factor 8 LIPOGENESIS Non-alcoholic fatty liver disease Peroxisome proliferator-activated receptorγ Transcriptional regulation 

分 类 号：R575.5[医药卫生—消化系统]