SCD1在2型糖尿病中对胰岛β细胞功能的保护作用及机制研究

The failure of pancreatic β cells plays a key role in the development and outcome of type 2 diabetes. Chronic hyperglycemia, commonly called “glucotoxicity”, is a major determinant of causing β-cell failure. The downregulation of MafA expression links glucotoxicity to pancreatic β-cell dysfunction. However, the molecular mechanism of high glucoe regulating MafA expression in pancreatic β cells is unclear. Our preliminary results showed that stearoyl-CoA desaturase 1 (SCD1) positively regulated MafA expression. High gluocse treatment resulted in a decrease of SCD1 expression in β cells. SCD1 overexpression reversed the decrease of MafA expression in β cells treated with high gluocse. Further studies showed that SCD1 directly interactd with MafA and protected MafA against ubiquitylation and degradation. SCD1 mRNA and protein level was significantly decreased in islets from db/db mice compared to control mice. In β cells, interference of SCD1 impaired insulin synthesis and secretion. As a result, we speculated that SCD1 played an important role in β cell function. Downregulation of SCD1 expression contributed to the decrease of SCD1 in β cells treated with high glucose. In this study, we aim to demonstrate the role and mechanism of SCD1 in pancreatic β-cell function in type 2 diabetes using a series of in vivo and in vitro technology. And we will further explore the novel mechanism of pancreatic β-cell glucotoxicity, trying to provide a potential target for the treatment of type 2 diabetes in the future.

胰岛β细胞功能障碍是2型糖尿病发生发展的核心环节，糖毒性是造成β细胞损伤的重要机制。转录因子MafA的表达下降介导了糖毒性作用，但慢性高糖通过何种机制抑制MafA的表达目前仍不清楚。本课题前期研究显示，硬酯酰辅酶A去饱和酶1（SCD1）正向调控MafA的表达；慢性高糖刺激抑制SCD1的表达；过表达SCD1逆转慢性高糖刺激引起的MafA表达下降。SCD1可与MafA特异性结合并抑制MafA的泛素化降解。db/db小鼠胰岛中SCD1的表达降低；β细胞干扰SCD1显著抑制胰岛素的合成和分泌。由此，我们推测，SCD1是维持β细胞功能的重要分子，其表达下降可能介导糖毒性引起的MafA表达下降。该项目旨在细胞和动物水平上，在高糖等2型糖尿病环境中，研究SCD1对胰岛β细胞功能的影响及其作用机制。本项目的完成将有助于阐明2型糖尿病糖毒性的新机制，并可能为2型糖尿病的防治提供新的潜在的作用靶点。

催化饱和脂肪酸转化为单不饱和脂肪酸合成的关键酶—硬酯酰辅酶A去饱和酶1（SCD1）在糖尿病中的作用受到广泛关注，但其在胰岛β细胞功能中的确切作用并不清晰。因此，本项目主要研究SCD1在2型糖尿病中对胰岛β细胞功能的保护作用及相关机制。研究结果显示，糖尿病小鼠胰岛β细胞以及慢性高糖刺激的胰岛β细胞系，SCD1的表达水平均显著下降。进一步研究显示，糖毒性通过转录因子Ets-1下调SCD1的表达。过表达SCD1能够逆转慢性高糖刺激引起的β细胞功能障碍；胰岛β细胞特异性SCD1的knock-in小鼠（βSCD1KI/KI）能够改善髙脂喂养引起的糖耐量受损、能够增加血胰岛素水平并促进1相和2相胰岛素分泌。胰岛β细胞干扰SCD1抑制胰岛素的合成和分泌。分子机制研究显示：干扰SCD1下调MafA的蛋白表达水平，过表达SCD1能够逆转慢性高糖引起的MafA蛋白降解。SCD1通过组氨酸盒结构与MafA进行相互作用，并上调MafA的转录活性。此外，SCD1能够与靶向修饰MafA的E3泛素连接酶Hrd1相互作用，并抑制Hrd1对MafA的泛素化修饰。我们还发现，过表达SCD1能够改善糖尿病小鼠胰岛移植物的功能。本项目意义在于揭示SCD1能够保护胰岛β细胞避免其损伤，为糖尿病的治疗提供可能的靶点。