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.