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

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 recessiv...

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Published in:Journal of molecular cell biology 2022-12, Vol.14 (8)
Main Authors: 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
Format: Article
Language:English
Subjects:
1-Acylglycerol-3-Phosphate O-Acyltransferase - genetics
1-Acylglycerol-3-Phosphate O-Acyltransferase - metabolism
Animals
Fatty Liver - genetics
Fatty Liver - metabolism
Hepatocytes - metabolism
Mice
Perilipin-3
Triglycerides - metabolism
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Summary: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.
ISSN:1674-2788
1759-4685
DOI:10.1093/jmcb/mjac055