姜黄素激活Nrf2系统对抗线粒体氧化应激在其缓解胰岛素抵抗中的作用及机制研究

A high fat diet(HFD) induced -insulin resistance (IR) is tightly related to the incidence of diabetes mellitus (DM). However, the critical triggering mechanism of IR remains to be elucidated. Because there is a clearly causal relationship between the mitochondrial oxidative stress and IR, and furthermore, mitochondrial oxidative stress could also evoke other pathophysiological inhibitory mechanisms, such as,inflammatory response and endoplasmic reticulum (ER) stress resulting in IR, therefore, it is likely that mitochondrial oxidative stress plays a central and initiating role in HFD-induced IR. To test this hypothesis, the present project will utilize the IR models established in mice and insulin-sentivite cells to explore the role of mitochondrial oxidative stress in the initiating IR and to determine the impact of mitochandrial oxidative stress on inflammation and ER stress as well. In the previous studies, we have also discovered that the endogenous regulator of anti-oxidative system-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays an important role in insulin sensitivity, whereas curcumin exerted significant effects in both activation of Nrf2 and attenuation of IR. Therefore, it is conjectured that there is an important causal link between them. The current project will apply curcumin to modulate Nrf2 function combined with the specific molecular biology technique to silencing Nrf2 and superoxide dismutase specifically located in mitochondria in order to explore whether curcumin could sensitize insulin action via the activation of Nrf2 to protect against mitochondrial oxidative stress. This study is expected to unveil the critical mechanism(s) of HFD-induced IR and major mechanism of the insulin sensitization exerted by curcumin, therefore providing a theoretical and experimental basis of a novel drug target for the treatment of DM.

高脂饮食造成的胰岛素抵抗（IR）与糖尿病发病关系十分密切，但关键触发机制尚未阐明。线粒体氧化应激与IR有明确因果关系，还可能诱发炎症反应以及内质网应激等其它IR病理机制。因此，线粒体氧化应激可能在高脂诱导IR中起中心和始动作用。为验证这一假设，本课题将以小鼠和胰岛素靶细胞IR为模型，探讨线粒体氧化应激的IR始动作用，并检查其对炎症、内质网应激影响。在前期工作中我们还发现内源性抗氧化系统Nrf2的功能对胰岛素敏感性有重要作用，而姜黄素则具有明显的激活Nrf2和改善IR效应,因此推论二者具有重要的因果关系。本课题将利用姜黄素对Nrf2功能的进行调控，并采用特异的分子生物学手段沉默细胞Nrf2和线粒体超氧化物歧化酶，以探讨姜黄素是否通过Nrf2对抗线粒体氧化应激从而起到增强胰岛素敏感性作用。研究可望揭示高脂诱导IR关键机制，发现姜黄素改善IR的主要机理，为糖尿病治疗新的靶标选择奠定理论实验基础。

胰岛素敏感组织在高脂诱导IR形成早期存在普遍的氧化应激状态，尤其是肌肉组织Nrf2系统功能的损害可能对IR起始起重要作用。此外，我们的工作证明氧化应激无论在整体小鼠还是在离体培养肝细胞均能诱导炎症和内质网应激，提示其在损害胰岛素信号传导机理方面起中心作用。对于姜黄素调控IR机理的研究工作表明，姜黄素通过激活Nrf2系统改善线粒体氧化应激在其改善胰岛素抵抗机理中发挥重要作用，而这一作用是主要通过抑制线粒体氧化应激以及钙超载激发的线粒体分裂以及炎症诱导的PTEN蛋白从而增强PI3K/PKB信号而实现的。.此外，在动物IR和人体糖尿病情况下，我们的工作表明姜黄素干预可以减轻内毒素血症，并激活Nrf2抗氧化系统；而姜黄素正是通过抑制炎症激活的Keap1表达抑制Nrf2蛋白酶体降解，从而激活Nrf2系统功能。.因此，我们的工作深入阐释了姜黄素治疗胰岛素抵抗的分子机理并为高脂诱导胰岛素产生的氧化应激假说提供了进一步证据，并提出肌肉Nrf2功能的早期损害造成的肌肉氧化应激可能的重要作用。研究不仅深化了胰岛素抵抗发病机理的了解，更为姜黄素的临床应用转化提供了分子水平的理论依据。