Knockdown of hepatocyte Perilipin-3 mitigates hepatic steatosis and steatohepatitis caused by hepatocyte CGI-58 deletion in mice

作者全名："Bao, Xinyu; Ma, Xiaogen; Huang, Rongfeng; Chen, Jianghui; Xin, Haoran; Zhou, Meiyu; Li, Lihua; Tong, Shifei; Zhang, Qian; Shui, Guanghou; Deng, Fang; Yu, Liqing; Li, Min-Dian; Zhang, Zhihui"

作者地址："[Bao, Xinyu; Ma, Xiaogen; Huang, Rongfeng; Chen, Jianghui; Xin, Haoran; Zhou, Meiyu; Li, Lihua; Li, Min-Dian; Zhang, Zhihui] Army Med Univ, Southwest Hosp, Ctr Circadian Metab & Cardiovasc Dis, Dept Cardiovasc Med, Chongqing 400038, Peoples R China; [Chen, Jianghui; Tong, Shifei] Chongqing Med Univ, Affiliated Hosp 3, Dept Cardiol, Chongqing 401120, Peoples R China; [Zhang, Qian] Army Med Univ, Southwest Hosp, Dept Gen Med, Chongqing 400038, Peoples R China; [Shui, Guanghou] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol Dev Biol, Beijing 100101, Peoples R China; [Deng, Fang] Army Med Univ, Coll High Altitude Mil Med, Dept Pathophysiol, Chongqing 400038, Peoples R China; [Deng, Fang] Minist Educ China, Key Lab Extreme Environm Med, Chongqing 400038, Peoples R China; [Deng, Fang] PLA, Key Lab High Altitude Med, Chongqing 400038, Peoples R China; [Deng, Fang] Univ Maryland, Dept Med, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA"

通信作者："Zhang, ZH (通讯作者)，Army Med Univ, Southwest Hosp, Ctr Circadian Metab & Cardiovasc Dis, Dept Cardiovasc Med, Chongqing 400038, Peoples R China."

来源：JOURNAL OF MOLECULAR CELL BIOLOGY

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000936654600001

JCR分区：Q2

影响因子：5.5

年份：2022

卷号：14

期号：8

开始页：　

结束页：　

文献类型：Article

关键词：lipid droplet; lipolysis; rare human disease; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; Chanarin-Dorfman syndrome

摘要："Comparative gene identification-58 (CGI-58), also known as alpha/beta hydrolase domain containing 5, is the co-activator of adipose triglyceride lipase that hydrolyzes triglycerides stored in the cytosolic lipid droplets. Mutations in CGI-58 gene cause Chanarin-Dorfman syndrome (CDS), an autosomal recessive neutral lipid storage disease with ichthyosis. The liver pathology of CDS manifests as steatosis and steatohepatitis, which currently has no effective treatments. Perilipin-3 (Plin3) is a member of the Perilipin-ADRP-TIP47 protein family that is essential for lipid droplet biogenesis. The objective of this study was to test a hypothesis that deletion of a major lipid droplet protein alleviates fatty liver pathogenesis caused by CGI-58 deficiency in hepatocytes. Adult CGI-58-floxed mice were injected with adeno-associated vectors simultaneously expressing the Cre recombinase and microRNA against Plin3 under the control of a hepatocyte-specific promoter, followed by high-fat diet feeding for 6 weeks. Liver and blood samples were then collected from these animals for histological and biochemical analysis. Plin3 knockdown in hepatocytes prevented steatosis, steatohepatitis, and necroptosis caused by hepatocyte CGI-58 deficiency. Our work is the first to show that inhibiting Plin3 in hepatocytes is sufficient to mitigate hepatocyte CGI-58 deficiency-induced hepatic steatosis and steatohepatitis in mice."

基金机构：National Natural Science Foundation of China [81873663]

基金资助正文：This work was supported by the National Natural Science Foundation of China (81873663 to Z.Z.).