联系肥胖“代谢转换”与胰岛素抵抗的纽带--- p53转录激活PANK1/miRNA103/107的关键作用

Chronic diseases, such as heart disease, stroke, cancer, chronic respiratory diseases and diabetes, have been by far the leading cause of mortality in the world, representing 60% of all deaths. Obesity is the common risk factor of the chronic disease and severely obese people have insulin resistance which is the core pathological mechanism of the chronic disease. Our preliminary data and previous studies have demonstrated that people with obesity showed restrained glycolysis and enhanced fatty acid oxidation which is the so-called "metabolic reprogramming". However, the relationship between "metabolic reprogramming" and insulin resistance is not yet clear. Our recent studies found that the expression of PANK1 which is the key enzyme of fatty acid oxidation increased. Interestingly, miRNA103/107 which contributes to insulin resistance locates in introns of the gene encoding PANK1 and p53 directly activates PANK1 expression at transcription level. The purpose of this study was firstly to confirm the correlation of the "metabolic reprogramming" and insulin resistance in animal model with obesity; secondly, to test transcriptional activation of PANK1/miRNA103/107 by p53 in primary cell induced by palmitate acid treatment; finally, with the application of genetic knockout model and pharmacological methods to further verify the critical role of transcriptional activation of PANK1/miRNA103/107 by p53 initiate the development of insulin resistance in obese animal model. This study is expected to reveal a novel mechanism which dominate vicious cycle of "metabolic reprogramming" and insulin resistance and provide theoretic basis and therapeutic targets for the treatment of obesity related diseases.

肥胖是众多慢性疾病共同的危险因素。肥胖患者能量利用方式发生转变，即糖酵解受到抑制而脂肪酸氧化加强，称之“代谢转换”，且肥胖患者大多存在胰岛素抵抗（IR）。然而，“代谢转换”与IR间的关系尚不清楚。我们前期实验结果表明，调节脂肪酸氧化的关键酶PANK1在肥胖小鼠肝脏中表达显著增加。有趣的是，具有促发IR作用的miRNA103/107位于编码PANK1基因的内含子区且p53可转录激活PANK1表达。基于此，本课题提出p53转录共激活PANK1/miRNA103/107可能是联系“代谢转换”与IR的关键机制。本课题拟验证“代谢转换”与IR相互促进的关系，进一步证实高脂处理可诱导p53转录激活PANK1/miRNA103/107，并利用基因敲除以及药理学手段逐步阐明上述通路在联系“代谢转换”与IR中的关键作用。本研究将揭示“代谢转换”与IR恶性循环、相互促进的机制，为肥胖相关疾病提供潜在治疗靶点。

长期高脂饮食可引起肥胖和胰岛素抵抗，而胰岛素抵抗是包括二型糖尿病在内的代谢性疾病及心血管疾病的“共同土壤”。以往报道认为，高脂饮食引起胰岛素抵抗的机制包括过度的脂质堆积、氧化应激增加以及巨噬细胞产生炎症因子增多。研究发现，高脂饮食可导致糖酵解减弱而脂肪酸氧化增强。然而，高脂饮食引起胰岛素抵抗的根本原因尚未完全阐明。本研究发现，给予小鼠16周高脂饮食可显著增加肝脏PANK1表达水平，且PANK1参与了棕榈酸钠处理肝细胞引起的代谢转换。在棕榈酸钠处理下，位于PANK1内含子区的miR-107通过靶向降解小凹蛋白caveolin-1增加胰岛素受体β稳定性从而引起胰岛素抵抗。此外，本研究发现，高脂饲养的小鼠肝脏与棕榈酸钠处理的肝细胞P53表达均显著增加，激动P53可在转录水平提高PANK1与miR-107表达并分别引起代谢转换与胰岛素抵抗。相反，抑制P53可显著减轻棕榈酸钠引起的代谢转换与胰岛素抵抗。本研究揭示了P53一种全新的代谢调节机制，并阐明了PANK1与其内含子区的miRNA在代谢调节中具有各自相对独立的作用。