丙酮酸脱氢酶激酶4在多囊卵巢综合征糖代谢紊乱中的作用及其机制研究

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorder and metabolic disorders in women of reproductive age. The abnormal glucose metabolism in PCOS patients mainly includes insulin resistance (IR) and hyperinsulinemia. The incidence of PCOS patients with impaired glucose tolerance is 10% in reproductive-aged women. To understand the pathogenesis of PCOS, expand clinical treatment and prevent the complications, the illumination of the mechanism of glucose metabolism disorders is very important. Using metabolomics analysis, our previous study demonstrated that the reaction of the glycolytic product into tricarboxylic acid cycle is limited in PCOS patients, and the activity of the key enzyme pyruvate dehydrogenase (PDC) may be inhibited. Studies have shown that PDC activity is down-regulated by pyruvate dehydrogenase kinase (PDK), and PDK4 expression in ovarian and peripheral tissues in PCOS is significantly increased. Which may inhibit the activity of PDC in mitochondria, limit the involvement of pyruvate into tricarboxylic acid, Oxidative metabolism, leading to reduced glucose tolerance eventually. In this study, we will study the role and molecular mechanism of PDK4 in the carcinogenesis of glucose metabolism disorder in PCOS patients, and provide the theoretical and application basis for the development of PCOS clinical therapeutic target.

多囊卵巢综合征(PCOS)是育龄期女性最常见的内分泌紊乱和代谢障碍性疾病，其糖代谢异常主要表现为胰岛素抵抗(IR)及高胰岛素血症，PCOS患者糖耐量减低发生率占育龄妇女的10%，阐明IR及糖代谢紊乱的发生机制对于理解PCOS的发病机理、拓展临床治疗及预防其并发症具有重要意义。本课题组前期利用代谢组学分析发现PCOS患者中调控糖酵解产物进入三羧酸循环的反应被限制，其中关键酶丙酮酸脱氢酶(PDC)的活性可能受到抑制。研究表明，PDC活性受丙酮酸脱氢酶激酶(PDK)下调，而PCOS卵巢及外周组织中PDK4表达显著升高，因而可能通过抑制线粒体内PDC活性，限制丙酮酸进入三羧酸循环，阻碍葡萄糖氧化代谢，导致糖耐量减低。本课题拟从临床标本检测、到细胞水平体外研究、到动物模型体内研究，探讨PDK4在PCOS糖代谢紊乱发生中的作用及其分子机制，为PCOS临床治疗靶点的开发提供理论基础及应用依据。