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

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。

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.