SIRT1/PGC1α-SIRT3-线粒体复合体I通路对高脂饮食骨骼肌胰岛素敏感性的影响及其机制研究

High-fat diet (HFD) induced oxidative stress and mitochondrial dysfunction are both very important in the development of Insulin resistant (IR). SIRT1/PGC1α could play a critical role in anti-oxidation and mitochondrial biogenesis, which is associated with the pathophysiological process of IR. However, the intrinsic mechanism has not yet been clear. Previous studies suggested that, the decreased expression of SIRT3, which also belongs to the Sirtuins members as SIRT1, was closely related to IR. In addition, SIRT3 could regulate the acetylation of mitochondrial complex I. Moreover, mitochondrial complex I is the main site for the generation of reactive oxygen species (ROS). Therefore, we speculated that increasing mitochondrial complex I through the up-regulation of SIRT3 expression may be the root for the improvement of IR by SIRT1/PGC1α. We intend to dynamically observe the changes of SIRT1/PGC1α, SIRT3, mitochondrial complex I and other functions of mitochondria in HFD rats. Besides, we intend to regulate SIRT1/PGC1α and SIRT3 in two directions, and observe the changes of mitochondrial complex I, oxidative stress, lipid metabolism and insulin sensitivity. Therefore, we could explore the internal mechanism and the important role of SIRT1/PGC1α-SIRT3- mitochondrial complex I pathway in the improvement of skeletal muscle IR in HFD rats, thus providing new ideas for the prevention and treatment of diseases related for IR during the nutrition promotion process.

高脂饮食所致氧化应激及线粒体功能下降是胰岛素抵抗形成的重要原因。SIRT1/PGC1α在抗氧化及线粒体生物发生等与胰岛素抵抗相关的病理生理过程中起至关重要的作用，但其机制未明。研究提示：与SIRT1同为Sirtuins 成员的SIRT3表达下降与胰岛素抵抗密切相关，且SIRT3可改变线粒体复合物Ⅰ乙酰化水平；而线粒体复合体I正是ROS产生的关键部位。因此，我们推测通过SIRT3影响线粒体复合体I是SIRT1/PGC1α改善胰岛素抵抗的根结。本课题拟动态观察高脂模型SIRT1/PGC1α、SIRT3、线粒体复合体I及线粒体各功能的改变；双向调节SIRT1/PGC1α、SIRT3的表达，观察线粒体复合体I、氧化应激、脂代谢及胰岛素敏感性的改变。据此阐明SIRT1/PGC1α-SIRT3-线粒体复合体I通路在改善骨骼肌胰岛素抵抗中的作用及机制，为营养提升过程中胰岛素抵抗相关疾病防治提供新思路。

高脂饮食极易导致胰岛素抵抗且与氧化应激及线粒体功能异常密切相关。本研究通过在体、离体转染实验，证实SIRT1/PGC1α-SIRT3-线粒体复合物1通路和高脂饮食骨骼肌胰岛素敏感性的关系。结果发现（1）在高脂饮食诱导的胰岛素抵抗大鼠模型中，骨骼肌组织SIRT1过表达可通过上调骨骼肌肌膜和肌纤维间线粒体AMPK、PGC-1α和SIRT3的表达水平，促进线粒体的生物合成，增强抗氧化酶活性，继而提高骨骼肌胰岛素敏感性，且这些作用的实现主要依赖于SIRT1-SIRT3-线粒体复合物I途径；（2）体外研究发现，在高糖诱导的骨骼肌细胞胰岛素抵抗模型中，SIRT1同样可以通过SIRT1-SIRT3-线粒体复合物I途径降低氧化应激和线粒体功能障碍，改善高糖诱导的胰岛素抵抗。此外，本研究拓展观察了（1）SIRT1 激动剂白藜芦醇对高脂饮食诱导胰岛素抵抗动物模型骨骼肌线粒体功能的影响，发现白藜芦醇能增加 SIRT1 的表达及活性，同时上调骨骼肌线粒体PGC-1α和SIRT3表达水平，通过改善骨骼肌肌膜下线粒体的 β 氧化平衡从而增加高脂饮食大鼠的胰岛素敏感性；（2）SIRT3可通过调控高脂条件下胰岛β细胞内质网伴侣分子GRP78乙酰化水平，进而下调内质网应激相关蛋白URE1、ATF6和CHOP表达水平，对内质网应激条件下的胰岛β细胞起到保护作用。

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