cAMP-AMPK-SIRT1通路在GLP-1受体激动剂改善肝脏脂肪变性中的作用机制

There is no drug approval for nonalcoholic fatty liver disease in clinical treatment at present. As a new hypoglycemic drug, GLP-1 receptor agonist has been proved by increasing evidence that it could improve lipid deposition in liver effectively. By activating GLP-1 receptor on hepatocytes, GLP-1 receptor agonist such as exenatide alleviates hepatocyte steatosis and upregulates SIRT1 expression simultaneously. The specific mechanism underlying is still unclearly, probably it is via cAMP signal transmission. SIRT1 is a kind of type III Histone Deacetylases, its activation depends on NAD+ and it is involved in lipid metabolism in liver. Our previous research found that SIRT1+/- mice could develop more serious liver steatosis compared with wild-type mice after high-fat diet induction. After GLP-1 receptor agonist treatment, liver steatosis could be reversed in wild-type mice, while it could not in case of SIRT1+/- mice, indicating that SIRT1 may mediate this attenuating liver steatosis effect of GLP-1 receptor agonist. We presume that cAMP, as a second messenger molecule, enlarges GLP-1 receptor agonist's effect and acts on downstream EPAC1 and AMPK, makes NAD+ synthesis increase, activates SIRT1 and leads to liver steatosis improving.

目前尚无药物正式批准用于非酒精性脂肪肝病的临床治疗，GLP-1受体激动剂作为新型降糖药，研究表明其改善肝脏脂质沉积的作用亦十分显著。肝细胞上具有GLP-1受体，激活它可减轻肝细胞的脂肪变性并上调SIRT1的表达，这一作用的具体机制尚不明确，可能通过cAMP的信号传递。SIRT1是一种组蛋白去乙酰化酶，其激活依赖于核内的NAD+，可参与肝脏的脂质代谢。我们的前期研究发现SIRT1+/-小鼠相比野生型对照可饮食诱导出更为严重的肝脏脂肪变性；经GLP-1受体激动剂干预后，野生型的肝脏脂肪变性可被逆转，而SIRT1+/-小鼠的则无明显改善，提示SIRT1介导了GLP-1受体激动剂的这一效应。我们推测，cAMP作为第二信使分子将GLP-1受体被激活的效应放大，并作用于下游的Epac1、AMPK，使得核内的NAD+合成增加、激活SIRT1，从而减轻肝细胞的脂质沉积。

针对“cAMP-AMPK-SIRT1通路在GLP-1受体激动剂exenatide改善肝脏脂肪变性中的作用机制”，我们结合多种动物模型和体外细胞模型，用GLP-1受体激动剂exenatide对高脂饮食诱导的非酒精性脂肪肝模型和棕榈酸诱导的肝细胞脂肪变性模型进行干预，在前期研究基础上重点研究了AMPK-SIRT1通路在该干预过程中的重要作用和具体机制，主要研究结果包括：发现了新型降糖药物GLP-1受体激动剂exenatide改善肝脏脂肪沉积和肝脏内质网应激的病理生理新机制，即证实exenatide可通过上调AMPK-SIRT1通路来减轻高脂饮食诱导的脂肪沉积和内质网应激，改善胰岛素抵抗，为GLP-1 受体激动剂临床应用于2 型糖尿病合并脂肪肝的治疗提供了深入的理论依据。此外发现在SIRT1基因缺陷小鼠中，饮食诱导的肥胖和胰岛素抵抗与其棕色脂肪功能退化相关，该研究进一步强调了SIRT1在肥胖相关的代谢紊乱中的有益保护作用。我们还阐明了GLP-1受体激动剂exenatide减重的新机制，即exenatide可通过激活SIRT1促进内脏白色脂肪的棕色化改变从而减轻体重，为GLP-1受体激动剂在临床中的减重作用提供了新的机制视角，并为防治肥胖提供了新的靶标；此外，还发现在高脂饮食诱导的肥胖状态下，GLP-1受体激动剂exenatide可通过减轻肥胖所致的炎症来改善雄性小鼠的精子质量和活性，这提示GLP-1受体激动剂治疗可能具备改善肥胖糖尿病男性精子质量的额外获益。