Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
PLoS One. 2012;7(2):e31394. doi: 10.1371/journal.pone.0031394. Epub 2012 Feb 17.
The effects of exendin-4 on Sirt1 expression as a mechanism of reducing fatty liver have not been previously reported. Therefore, we investigated whether the beneficial effects of exendin-4 treatment on fatty liver are mediated via Sirt1 in high-fat (HF) diet-induced obese C57BL/6J mice and related cell culture models. Exendin-4 treatment decreased body weight, serum free fatty acid (FA), and triglyceride levels in HF-induced obese C57BL/6J mice. Histological analysis showed that exendin-4 reversed HF-induced hepatic accumulation of lipids and inflammation. Exendin-4 treatment increased mRNA and protein expression of Sirt1 and its downstream factor, AMPK, in vivo and also induced genes associated with FA oxidation and glucose metabolism. In addition, a significant increase in the hepatic expression of Lkb1 and Nampt mRNA was observed in exendin-4-treated groups. We also observed increased expression of phospho-Foxo1 and GLUT2, which are involved in hepatic glucose metabolism. In HepG2 and Huh7 cells, mRNA and protein expressions of GLP-1R were increased by exendin-4 treatment in a dose-dependent manner. Exendin-4 enhanced protein expression of Sirt1 and phospho-AMPKα in HepG2 cells treated with 0.4 mM palmitic acid. We also found that Sirt1 was an upstream regulator of AMPK in hepatocytes. A novel finding of this study was the observation that expression of GLP-1R is proportional to exendin-4 concentration and exendin-4 could attenuate fatty liver through activation of Sirt1.
外源性胰高血糖素样肽-1 对 Sirt1 表达的影响作为减轻脂肪肝的机制尚未被报道。因此，我们研究了外源性胰高血糖素样肽-1 治疗是否通过 Sirt1 介导在高脂肪（HF）饮食诱导肥胖 C57BL/6J 小鼠及其相关细胞培养模型中发挥作用。外源性胰高血糖素样肽-1 治疗降低了 HF 诱导肥胖 C57BL/6J 小鼠的体重、血清游离脂肪酸（FA）和甘油三酯水平。组织学分析表明，外源性胰高血糖素样肽-1 逆转了 HF 诱导的肝脏脂质蓄积和炎症。外源性胰高血糖素样肽-1 治疗增加了 Sirt1 及其下游因子 AMPK 的 mRNA 和蛋白表达，体内也诱导了与 FA 氧化和葡萄糖代谢相关的基因。此外，在接受外源性胰高血糖素样肽-1 治疗的组中观察到 Lkb1 和 Nampt mRNA 的肝表达显著增加。我们还观察到磷酸化 Foxo1 和 GLUT2 的表达增加，这涉及肝脏葡萄糖代谢。在 HepG2 和 Huh7 细胞中，外源性胰高血糖素样肽-1 以剂量依赖的方式增加 GLP-1R 的 mRNA 和蛋白表达。外源性胰高血糖素样肽-1 增强了 0.4 mM 棕榈酸处理的 HepG2 细胞中 Sirt1 和磷酸化 AMPKα的蛋白表达。我们还发现 Sirt1 是肝细胞中 AMPK 的上游调节因子。本研究的一个新发现是观察到 GLP-1R 的表达与外源性胰高血糖素样肽-1 浓度成正比，外源性胰高血糖素样肽-1 可以通过激活 Sirt1 减轻脂肪肝。
