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Knockdown of hepatocyte Perilipin-3 mitigates hepatic steatosis and steatohepatitis caused by hepatocyte CGI-58 deletion in mice
Xinyu Bao1 , Xiaogen Ma1 , Rongfeng Huang1 , Jianghui Chen1,2 , Haoran Xin1 , Meiyu Zhou1 , Lihua Li1 , Shifei Tong2 , Qian Zhang3 , Guanghou Shui4 , Fang Deng5,6,7 , Liqing Yu8 , Min-Dian Li1 , Zhihui Zhang1,*
1Department of Cardiovascular Medicine, Center for Circadian Metabolism and Cardiovascular Disease, Southwest Hospital, Army Medical University, Chongqing 400038, China
2Department of Cardiology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
3Department of General Medicine, Southwest Hospital, Army Medical University, Chongqing 400038, China
4State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
5Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China
6Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing 400038, China
7Key Laboratory of High Altitude Medicine, PLA, Chongqing 400038, China
8Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
*Correspondence to:Zhihui Zhang ,
J Mol Cell Biol, Volume 14, Issue 8, August 2022, mjac055,

Comparative gene identification-58 (CGI-58), also known as α/β 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.