Sirt3在高糖环境下胰腺β细胞去分化中的作用和机制及安石榴苷的干预效应

Pancreatic beta-cell dedifferentiation are thought to be an important pathophysiological foundation in the failure of beta-cell function of diabetes mellitus type 2 (T2DM). The deficiency of FoxO1 (one member of Forkhead protein family) function played an key role in the beta-cell dedifferentiation under high glucose condition, but the mechanism is unclear. In our research, we think that silent mating type information regulation 2 homolog 3(Sirt3) , one of Class Ⅲ deacetylases, might be the key factor contributing to beta-cell dedifferentiation, which is closely associated with FoxO1 function though two pathway. In Specific, under high glucose conditions, decreased Sirt3, on one hand, makes the loss of FoxO1 quantity though the increased acetylation of Skp2 and its activity as an ubiquitin-conjugating enzyme; on the other hand, decreased Sirt3 leads to the increased acetylation of FoxO1and thus the further deficiency of FoxO1 function. Both aspects contribute to the beta-cell dedifferentiation. Meanwhile, we found that punicalagin (a natural medicine) had an effect on dedifferentiation of beta-cell. Therefore, in this research we would like to illuminate the importance of Sirt3 on beta-cell function failure and its mechanisms, which will be helpful to provide a new therapeutic target for T2DM. Furthermore, we will also provide theoretical basis for T2DM treatment by clarifying the mechanisms of punicalagin as a preventer of beta-cell failure.

β细胞去分化是T2DM胰腺β细胞功能衰竭的重要病理生理基础，Forkhead蛋白家族成员FoxO1功能减退被认为是高糖环境下β细胞去分化的重要基础，但其调控机制未明。我们提出Ⅲ类去乙酰化酶Sirt3可能通过两条途径抑制了FoxO1的功能，是β细胞去分化的关键因素，即：高糖环境下，下调的Sirt3一方面通过增强S期激酶相关蛋白2（Skp2）的作用而使FoxO1总量降低；另一方面与FoxO1直接结合，进一步降低FoxO1的功能；双重作用引起了β细胞的去分化及细胞功能的衰竭。天然药物安石榴苷可能对胰腺β细胞去分化具有阻抑作用。本项目将揭示Sirt3在胰腺β细胞功能衰竭中的重要作用和机制，同时为将安石榴苷开发成为防治T2DM的新型天然药物提供理论基础和实验依据。

β细胞去分化是T2DM胰岛β细胞功能衰竭的重要病理生理基础，Forkhead蛋白家族成员FoxO1功能减退被认为是高糖环境下β细胞去分化的重要基础，但其调控机制未明。我们研究发现Ⅲ类去乙酰化酶Sirt3通过两条途径抑制了FoxO1的功能，是β细胞去分化的关键因素，即：高糖环境下，下调的Sirt3一方面通过增强S期激酶相关蛋白2（Skp2）的作用而使FoxO1总量降低；另一方面与FoxO1直接结合，进一步降低FoxO1的功能；双重作用引起了β细胞的去分化及细胞功能的衰竭。天然药物安石榴苷对胰岛β细胞去分化具有阻抑作用。同时我们发现黄酮类化合物槲皮素也可通过Sirt3而具有改善胰岛β细胞凋亡作用。本项目揭示了Sirt3在胰岛β细胞功能衰竭中的重要作用和机制，同时为将安石榴苷、槲皮素开发成为防治T2DM的新型天然药物提供理论基础和实验依据。