茶黄素通过线粒体生物合成途径改善高脂诱导肝胰岛素抵抗的作用机制

Targeting mitochondrial biogenesis and function has been recognized as a new strategy to improve insulin resistance (IR) in diabetes and obesity. Natural products with the activity of improving IR have received more and more attention due to their less side effects compared with drugs. Theaflavins are the major pigment which account for the quality and bioactivity of black tea. Our previous study showed theaflavins could significantly ameliorate IR in high-fat diet induced obese rats. However, the related mechanism is still unclear. We further found theaflavins obviously increased the mitochondrial DNA content in the palmitate-induced HepG2 cells, indicating mitochondria play an important role in improving IR by theaflavins. In the present study, we investigate the effects of theaflavins on IR and mitochondrial functions in the palmitate-induced HepG2 cells and C57BL/6J mice fed high-fat diet. Furthermore, the potential underlying mechanisms are explored by gene silencing and overexpression, co-Immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP). This study is of great interest to clarify the mechanisms of improving IR by black tea and theaflavins, and provide evidence of theaflavins as novel food functional components for amelioration of obesity-associated insulin resistance.

调节线粒体生物合成与功能被视作改善胰岛素抵抗的新策略。改善胰岛素抗性的天然活性物质相对于药物具有毒副作用小的优势，因而备受关注。茶黄素是影响红茶品质和生物活性的重要色素成分。本项目组前期研究表明茶黄素能够明显改善高脂诱导肥胖大鼠的胰岛素抵抗，但作用机制尚未明确。进而采用软脂酸诱导的人肝癌HepG2细胞模型发现，茶黄素能显著改善软脂酸引起的线粒体DNA含量减少，预示线粒体在茶黄素改善胰岛素抗性中具有重要作用。在此基础上，本项目拟采用软脂酸诱导的HepG2 细胞模型和高脂诱导的肥胖C57BL/6J小鼠模型，借助蛋白/染色质免疫共沉淀(CoIP和ChIP)、基因沉默和过表达等技术，系统研究茶黄素改善胰岛素抵抗的信号途径、调节线粒体生物合成及功能的分子机制以及二者间的联系。研究结果对阐释红茶和茶黄素改善胰岛素抵抗的作用机制具有理论意义，同时也为茶黄素作为改善胰岛素抗性的新食品功能因子提供科学参考。

调节线粒体生物合成和功能被视作改善胰岛素抵抗的新策略。改善胰岛素抗性的天然活性物质相对于药物具有毒副作用小的优势，因而广受关注。茶黄素是影响红茶品质和生物活性的重要色素成分。在高脂饮食加链脲霉素诱导的糖尿病小鼠中，茶黄素能够显著改善小鼠的葡萄糖耐受性、胰岛素耐受性、胰岛素抗性指数和敏感性指数；还能提高肝脏中线粒体DNA的相对含量。在软脂酸诱导的人肝癌HepG2细胞模型中，茶黄素能够显著提高细胞对葡萄糖的吸收，并增加增加GLUT4总蛋白和膜蛋白以及phosphor-Akt (Ser473)的蛋白水平，降低 IRS-1 在 Ser307的磷酸化。茶黄素显著改善软脂酸引起的线粒体相对DNA含量减少，并下调 PGC-1β mRNA 表达， 上调 PRC mRNA 表达。线粒体分裂抑制剂 Mdivi-1能够减弱茶黄素改善细胞胰岛素抵抗的能力，表明线粒体在茶黄素改善胰岛素抗性中具有重要作用。上述研究结果表明，茶黄素具有改善高脂诱导胰岛素抵抗的活性，线粒体在其中具有重要作用。茶黄素有望开发成保健食品或药品，以治疗或改善胰岛素抵抗相关的代谢性疾病。