RT Journal Article
SR Electronic
T1 The critical role of BTRC in hepatic steatosis as an ATGL E3 ligase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.15.516629
DO 10.1101/2022.11.15.516629
A1 Weiwei Qi
A1 Zhenzhen Fang
A1 Chuanghua Luo
A1 Honghai Hong
A1 Yanlan Long
A1 Zhiyu Dai
A1 Junxi Liu
A1 Yongcheng Zeng
A1 Ti Zhou
A1 Yong Xia
A1 Xia Yang
A1 Guoquan Gao
YR 2022
UL http://biorxiv.org/content/early/2022/11/16/2022.11.15.516629.abstract
AB Objective Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is one of the most common causes of liver dysfunction. ATGL is closely related to hepatic steatosis as the speed-limited triacylglycerol lipase. Nevertheless, the expression and regulation of ATGL in NAFLD remain unclear.Methods Using immunohistochemistry and qRT-PCR to detect the expression of ATGL and BTRC in different models with hepatic steatosis. Co-IP evaluated the binding of ATGL and BTRC. Knockdown of BTRC employed by adenoviruses and then analyzed the ATGL expression, triglyceride levels, and lipid droplets accumulation.Results Our results revealed that ATGL protein level was decreased in animal and cellular models of hepatic steatosis and the liver tissues of cholangioma/hepatic carcinoma patients with hepatic steatosis, while the ATGL mRNA level had hardly changed; which means the decreased ATGL mainly degraded through the proteasome pathway. BTRC was identified as the E3 ligase for ATGL, up-regulated, and negatively correlated with ATGL level. Moreover, adenovirus-mediated knockdown of BTRC ameliorated hepatic steatosis via up-regulating ATGL level.Conclusions Our study demonstrates a crucial role of elevated BTRC in hepatic steatosis through promoting ATGL proteasomal degradation as a new ATGL E3 ligase and suggests BTRC may serve as a potential therapeutic target for NAFLD.Funding This study was supported by The National Natural Science Foundation of China (Grants 82070888, 82070882, 82100917, 81872165, 82273116, 82203661, 81901557 and 81902693); Key Project of Nature Science Foundation of Guangdong Province, China (Grant 2019B1515120077); National Key R&D Program of China (Grant 2018YFA0800403); Guangdong Special Support Program for Young Top Scientist (Grant 201629046); Guangdong Natural Science Fund (Grant 2019A1515011810, 2021A1515010434, 2022A1515012423 and 2022A1515012513); Key Sci-Tech Research Project of Guangzhou Municipality (Grants 202201010820) Fundamental Research Funds for the Central Universities (Grant 50000-31620106); China Postdoctoral Science Foundation (Grant 2021M703679, 2020M683110).Competing Interest StatementThe authors have declared no competing interest.