SIRT1 Mediates the Effect of GLP-1 Receptor Agonist Exenatide on Ameliorating Hepatic Steatosis
SIRT1 Mediates the Effect of GLP-1 Receptor Agonist Exenatide on Ameliorating Hepatic Steatosis
复制标题
SIRT1 介导 GLP-1 受体激动剂艾塞那肽改善肝脂肪变性的作用
DOI：
10.2337/db14-0263
复制
发表时间：
2014-11-01
期刊：
影响因子：
7.7
通讯作者：
Weng, Jianping
中科院分区：
文献类型：
--
作者：
Xu, Fen;Li, Zhuo;Weng, Jianping
GLP-1和肠促胰岛素模拟物，如艾塞那肽，已被证明在体内和体外减轻肝细胞脂肪变性，但具体的潜在机制尚不清楚。SIRT1是一种依赖NAD+的蛋白去乙酰化酶，已被越来越多的研究认为是肝脏脂质稳态的重要调节因子。在这里，我们推测SIRT1可能介导GLP-1受体激动剂艾塞那肽（exendin-4）改善肝脂肪变性的作用。在高脂肪饮食刺激的雄性SIRT1+/−小鼠及其野生型（WT）幼崽中，我们发现，在WT组显著改善的脂质沉积和肝脏炎症在SIRT1+/−小鼠中减少了。此外，在艾塞那肽治疗后，WT组SIRT1和磷酸化AMPK的蛋白表达上调，而脂肪生成相关蛋白，包括SREBP-1c和PNPLA3的表达下调。然而，在SIRT1+/−小鼠中没有观察到这些变化。在HepG2细胞中，当SIRT1 RNA干扰使SIRT1沉默时，棕榈酸盐诱导的exendin-4逆转脂质沉积受到阻碍。我们的数据表明SIRT1介导艾塞那肽改善肝脂肪变性的作用，提示GLP-1受体激动剂可能作为非酒精性脂肪性肝病（NAFLD）的潜在药物，特别是2型糖尿病合并NAFLD， SIRT1可能是NAFLD的治疗靶点。
GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis in vivo and in vitro, but the specific underlying mechanism is unclear. SIRT1, an NAD+-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of the GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8 weeks of exenatide treatment in male SIRT1+/− mice challenged with a high-fat diet and their wild-type (WT) littermates, we found that lipid deposition and inflammation in the liver, which were improved dramatically in the WT group, diminished in SIRT1+/− mice. In addition, the protein expression of SIRT1 and phosphorylated AMPK was upregulated, whereas lipogenic-related protein, including SREBP-1c and PNPLA3, was downregulated in the WT group after exenatide treatment. However, none of these changes were observed in SIRT1+/− mice. In HepG2 cells, exendin-4–reversed lipid deposition induced by palmitate was hampered when SIRT1 was silenced by SIRT1 RNA interference. Our data demonstrate that SIRT1 mediates the effect of exenatide on ameliorating hepatic steatosis, suggesting the GLP-1 receptor agonist could serve as a potential drug for nonalcoholic fatty liver disease (NAFLD), especially in type 2 diabetes combined with NAFLD, and SIRT1 could be a therapeutic target of NAFLD.