Non-alcoholic fatty liver disease(NAFLD),characterized by hepatic steatosis,is one of the commonest causes of liver dysfunction.Adipose triglyceride lipase(ATGL)is closely related to lipid turnover and hepatic steatos...Non-alcoholic fatty liver disease(NAFLD),characterized by hepatic steatosis,is one of the commonest causes of liver dysfunction.Adipose triglyceride lipase(ATGL)is closely related to lipid turnover and hepatic steatosis as the speed-limited triacylglycerol lipase in liver lipolysis.However,the expression and regulation of ATGL in NAFLD remain unclear.Herein,our results showed that ATGL protein levels were decreased in the liver tissues of high-fat diet(HFD)-fed mice,naturally obese mice,and cholangioma/hepatic carcinoma patients with hepatic steatosis,as well as in the oleic acid-induced hepatic steatosis cell model,while ATGL mRNA levels were not changed.ATGL protein was mainly degraded through the proteasome pathway in hepatocytes.Beta-transducin repeat containing(BTRC)was upregulated and negatively correlated with the decreased ATGL level in these hepatic steatosis models.Consequently,BTRC was identified as the E3 ligase for ATGL through predominant ubiquitination at the lysine 135 residue.Moreover,adenovirus-mediated knockdown of BTRC ameliorated steatosis in HFD-fed mouse livers and oleic acid-treated liver cells via upregulating the ATGL level.Taken together,BTRC plays a crucial role in hepatic steatosis as a new ATGL E3 ligase and may serve as a potential therapeutic target for treating NAFLD.展开更多
基金supported by grants from the National Natural Science Foundation of China(82070888,82070882,82100917,82273116,82203661,81901557,and 81902693)the National Key R&D Program of China(2018YFA0800403)+3 种基金Guangdong Special Support Program for Young Top Scientist(201629046)Guangdong Natural Science Fund(2021A1515010434,2022A1515012423,2022A1515012513,and 2023A1515010316)the Key Sci-Tech Research Project of Guangzhou Municipality(202201010820)China Postdoctoral Science Foundation(2021M703679 and 2020M683110).
文摘Non-alcoholic fatty liver disease(NAFLD),characterized by hepatic steatosis,is one of the commonest causes of liver dysfunction.Adipose triglyceride lipase(ATGL)is closely related to lipid turnover and hepatic steatosis as the speed-limited triacylglycerol lipase in liver lipolysis.However,the expression and regulation of ATGL in NAFLD remain unclear.Herein,our results showed that ATGL protein levels were decreased in the liver tissues of high-fat diet(HFD)-fed mice,naturally obese mice,and cholangioma/hepatic carcinoma patients with hepatic steatosis,as well as in the oleic acid-induced hepatic steatosis cell model,while ATGL mRNA levels were not changed.ATGL protein was mainly degraded through the proteasome pathway in hepatocytes.Beta-transducin repeat containing(BTRC)was upregulated and negatively correlated with the decreased ATGL level in these hepatic steatosis models.Consequently,BTRC was identified as the E3 ligase for ATGL through predominant ubiquitination at the lysine 135 residue.Moreover,adenovirus-mediated knockdown of BTRC ameliorated steatosis in HFD-fed mouse livers and oleic acid-treated liver cells via upregulating the ATGL level.Taken together,BTRC plays a crucial role in hepatic steatosis as a new ATGL E3 ligase and may serve as a potential therapeutic target for treating NAFLD.
