Abstract:
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.
摘要:
非酒精性脂肪性肝病(NAFLD),以肝脏脂肪变性为特征,是肝功能障碍最常见的原因之一。脂肪甘油三酯脂肪酶(ATGL)作为肝脏脂解中的限速三酰甘油脂肪酶,与脂质更新和肝脂肪变性密切相关。然而,ATGL在NAFLD中的表达和调节尚不清楚.在这里,我们的结果表明,ATGL蛋白水平在高脂饮食(HFD)喂养小鼠的肝脏组织中降低,自然肥胖的老鼠,和胆管瘤/肝癌患者肝脂肪变性,以及在油酸诱导的肝脂肪变性细胞模型中,而ATGLmRNA水平没有改变。肝细胞中ATGL蛋白主要通过蛋白酶体途径降解。在这些肝脂肪变性模型中,β-转导素重复序列(BTRC)上调,并与ATGL水平降低呈负相关。因此,BTRC通过在赖氨酸135残基处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敲除通过上调ATGL水平改善HFD喂养的小鼠肝脏和油酸处理的肝细胞的脂肪变性。一起来看,BTRC作为一种新的ATGLE3连接酶在肝脂肪变性中起着至关重要的作用,并且可能作为治疗NAFLD的潜在治疗靶点。