黄癸固体分散体调控iPLA2β/CL/Opa1稳定线粒体动力学改善胰岛β细胞功能的研究

Disruptions of mitochondrial dynamics contribute to the deterioration of beta-cell function in the progression of diabetes. Previous studies have shown that cardiolipin(CL) can regulate the mitochondrial dynamics by promoting Opa1 to form a functional dimer in a CL-dependent manner. Moreover, CL remodeling enzyme Group VIA Phospholipase A2 (iPLA2β) may participate in repair of oxidized cardiolipin (ox-CL). Thus, an abnormality of iPLA2β/CL/ Opa1 mediated disruption of mitochondrial dynamics may be involved in β-cells damage in T2DM. The drug regulating iPLA2β/CL/ Opa1 would reverse β-cell failure. Our previous studies have found that the Huang-Gui solid dispersion(HGSD) we generated can promote insulin release and suppress apoptosis in both insulin-producing MIN6 cells and in the β-cells of a mice model of T2DM induced by high fat diet combined with streptozotocin, which may be related to iPLA2β up-regulation. In addition, we have observed that HGSD may increase CL level. In this study, we will adopt iPLA2β silence and overexpression to examine how the iPLA2β/CL/Opa1 interaction may play an important role in the preservation of mitochondrial dynamics and the dysregulation of β-cell function in T2DM. The prevention of HGSD on β-cell injury, through regulation of the iPLA2β/CL/Opa1 mediated mitochondrial dynamics pathway, may provide a new therapeutic target to mitochondria for the treatment of T2DM.

线粒体动力学失衡是胰岛β细胞功能衰竭的始动因素，心磷脂（CL）调控Opa1是维持线粒体动力学平衡的重要环节，而钙非依赖型磷脂酶A2（iPLA2β）是修复氧化损伤CL的关键酶。因此，我们提出了iPLA2β/CL/Opa1通路异常导致线粒体动力学失衡，进而引起β细胞功能衰竭这一科学假说。前期工作基础已经证实黄癸固体分散体对2型糖尿病小鼠胰岛及MIN6胰岛细胞均具有保护作用，与上调iPLA2β有关，且增加心肌CL水平。本项目拟利用iPLA2β siRNA干扰、过表达及黄癸固体分散体的干预，阐明iPLA2β/CL/Opa1通路在稳定胰岛β细胞线粒体动力学中的关键作用以及黄癸固体分散体改善β细胞功能的分子机制。本项目将为2型糖尿病的靶向线粒体治疗提供新靶点，也为黄癸固体分散体的研发提供理论依据。