心磷脂重塑酶Tafazzin在高脂饮食诱导的心肌胰岛素抵抗中的作用和机制研究

Insulin resistance is an important pathology of diabetic cardiomyopathy. Mitochondria dysfunction contributes to insulin resistance. Cardiolipin(CL) is a key phospholipid which is a construct lipid of mitochondrial respiratory chain. Dysfunction of mitochondrial respiratory chain induces cardiac insulin resistance. In the process of CL synthesis, CL remodeling is the most important step which determines its activity. Tafazzin(TAZ) is a dispensible protein specific for CL remodeling and localized in mitochondrial. Deficiency of CL induces severe cardiac hypertrophy and mitochondrial dysfunction, however, TAZ KD cells were protected from mitochondrial apoptosis when presents with detrimental stimuli. But the regulatory mechanism of TAZ is still not clear. Our previous research work shows that TAZ level increased in cardiac tissue of high-fat diet induced insulin resistant animals compare to Low fat controls, Furthermore palmitic acid induces increased proton leak and decreased oxygen consumption capacity. Thus our hypothesis is that high fat diet induces TAZ increases, which result in increased dysfunction of mitochondrial and increase ROS production. Then ROS blocked downstream insulin signal by dysfunction of AKT. Our aim of this study was to evaluate relationship between TAZ and high-fat induced cardiac insulin resistance; Also, we want to find the upstream regulator of TAZ. Our purpose is to clarify TAZ's regulatory role in mechanism of high-fat diet induced insulin resistance, and provide an early diagnosis method and therapy target for diabetic cardiomyopathy.

线粒体功能失调是导致心肌胰岛素抵抗的主要原因。心磷脂(Cardiolipin, CL)是线粒体内膜特有的磷脂，病理性CL缺失及CL结构的改变往往伴随着线粒体形态改变和功能障碍。Tafazzin(TAZ)是CL合成过程中的关键酶，TAZ基因的突变能使CL重塑失败，从而导致严重的心肌肥大和线粒体功能障碍。但是在有害刺激条件下，TAZ的敲除又能抑制线粒体凋亡的发生。因此，TAZ可能是一把“双刃剑”，对不同环境因素起不同的作用。TAZ在心肌胰岛素抵抗中的作用尚未有报道。我们前期工作显示，高脂饮食诱导的胰岛素抵抗小鼠心肌TAZ水平明显上调，心肌细胞线粒体功能降低。因此推测，在高饱和脂肪酸存在的情况下，TAZ使CL重塑异常，导致线粒体呼吸链受损，线粒体功能下降，胰岛素抵抗发生。本课题拟研究TAZ在高脂饮食诱发心肌胰岛素抵抗中的作用以及其上游调控机制，为糖尿病心肌病早期监测及干预提供新思路和新靶点。

目前肥胖和超重是全球引起糖尿病的主要风险因素。不良的生活习惯和高脂肪高糖摄入又是引起肥胖的主要原因。线粒体是细胞产生能量和消耗营养物质的主要场所，是细胞能量的发电机，线粒体功能的正常维持是心肌细胞维持能量代谢的重要环节之一。本项目通过高脂饮食的动物模型和饱和脂肪酸诱导的胰岛素抵抗的细胞模型研究发现，长期的高脂肪饮食能够引起心肌细胞线粒体内膜的特异性蛋白tafazzin的表达变化并且诱导心肌细胞胰岛素抵抗的发生。这一变化是通过线粒体分裂蛋白DRP-1向线粒体募集所引起的，同时高脂饮食引起的心肌细胞内小RNA-miR-125b的降低是引起TAZ升高的原始因素。miR-125b能直接作用于tafazzin的3’UTR调控tafazzin的表达水平，从而调控DRP-1向线粒体的转位，调控线粒体的稳态平衡。因此，通过调控miR-125b的水平有望调控线粒体稳态从而改善心肌胰岛素抵抗的情况。