Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Department of Clinical Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510006, China.
J Mol Cell Biol. 2024 Apr 4;15(10). doi: 10.1093/jmcb/mjad064.
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.
非酒精性脂肪性肝病（NAFLD）以肝脂肪变性为特征，是最常见的肝功能障碍原因之一。脂肪甘油三酯脂肪酶（ATGL）与脂质周转和肝脂肪变性密切相关，是肝脏脂肪分解的限速三酰基甘油脂肪酶。然而，ATGL 在 NAFLD 中的表达和调节尚不清楚。在此，我们的结果表明，高脂肪饮食（HFD）喂养的小鼠、天然肥胖小鼠、伴有肝脂肪变性的胆管癌/肝癌患者以及油酸诱导的肝脂肪变性细胞模型的肝组织中 ATGL 蛋白水平降低，而 ATGL mRNA 水平没有改变。ATGL 蛋白主要通过肝细胞中的蛋白酶体途径降解。β-转导重复蛋白（BTRC）在这些肝脂肪变性模型中上调，并与 ATGL 水平降低呈负相关。因此，BTRC 通过赖氨酸 135 残基的主要泛素化被鉴定为 ATGL 的 E3 连接酶。此外，腺病毒介导的 BTRC 敲低通过上调 ATGL 水平改善了 HFD 喂养小鼠肝脏和油酸处理的肝细胞中的脂肪变性。综上所述，BTRC 作为一种新的 ATGL E3 连接酶，在肝脂肪变性中起着至关重要的作用，可能成为治疗 NAFLD 的潜在治疗靶点。
