Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
Hepatocyte TMEM16A Deletion Retards NAFLD Progression by Ameliorating Hepatic Glucose Metabolic Disorder
复制标题
肝细胞 TMEM16A 缺失通过改善肝葡萄糖代谢紊乱来延缓 NAFLD 进展
DOI：
10.1002/advs.201903657
复制
发表时间：
2020-03-20
期刊：
影响因子：
15.1
通讯作者：
Liang, Si-Jia
中科院分区：
文献类型：
--
作者：
Guo, Jia-Wei;Liu, Xiu;Liang, Si-Jia
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，其发病机制尚未完全确定。跨膜成员16A （TMEM16A）是Ca2+激活的氯离子通道（CaCC）的一个组成部分，最近被认为与代谢事件有关。在此，TMEM16A被证明负责肝细胞中的CaCC激活，并且在小鼠和NAFLD患者的肝组织中增加。小鼠肝细胞特异性消融TMEM16A可改善高脂饮食引起的肥胖、肝糖代谢紊乱、脂肪变性、胰岛素抵抗和炎症。相反，肝细胞特异性TMEM16A转基因小鼠表现出相反的表型。机制上，肝细胞TMEM16A与囊泡相关膜蛋白3 （VAMP3）相互作用，诱导其降解，抑制VAMP3/syntaxin 4和VAMP3/突触体相关蛋白23复合物的形成。这导致肝脏葡萄糖转运蛋白2 （GLUT2）易位和葡萄糖摄取受损。值得注意的是，VAMP3过表达抑制肝细胞TMEM16A阻断GLUT2易位、促进脂质沉积、胰岛素抵抗和炎症的功能。相反，VAMP3敲低逆转了TMEM16A下调的有益作用。本研究证实了TMEM16A在NAFLD中的作用，并提示抑制肝脏TMEM16A或破坏TMEM16A/VAMP3相互作用可能为NAFLD提供一种新的潜在治疗策略。
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease, and the mechanisms underpinning its pathogenesis have not been completely established. Transmembrane member 16A (TMEM16A), a component of the Ca2+-activated chloride channel (CaCC), has recently been implicated in metabolic events. Herein, TMEM16A is shown to be responsible for CaCC activation in hepatocytes and is increased in liver tissues of mice and patients with NAFLD. Hepatocyte-specific ablation of TMEM16A in mice ameliorates high-fat diet-induced obesity, hepatic glucose metabolic disorder, steatosis, insulin resistance, and inflammation. In contrast, hepatocyte-specific TMEM16A transgenic mice exhibit the opposite phenotype. Mechanistically, hepatocyte TMEM16A interacts with vesicle-associated membrane protein 3 (VAMP3) to induce its degradation, suppressing the formation of the VAMP3/syntaxin 4 and VAMP3/synaptosome-associated protein 23 complexes. This leads to the impairment of hepatic glucose transporter 2 (GLUT2) translocation and glucose uptake. Notably, VAMP3 overexpression restrains the functions of hepatocyte TMEM16A in blocking GLUT2 translocation and promoting lipid deposition, insulin resistance, and inflammation. In contrast, VAMP3 knockdown reverses the beneficial effects of TMEM16A downregulation. This study demonstrates a role for TMEM16A in NAFLD and suggests that inhibition of hepatic TMEM16A or disruption of TMEM16A/VAMP3 interaction may provide a new potential therapeutic strategy for NAFLD.