自噬介导BPA诱导的胰岛素抵抗及莱菔硫烷干预效应的作用机制研究

Bisphenol-A (BPA) is an ubiquitous chemical and recognized an endocrine disruptor associated with insulin resistance(IR) and diabetes mellitus. Growing evidence suggests that exposure to BPA induces IR and inflammation. It is reported that impaired autophagy contributes to insulin resistance and inflammation. However, no evidence indicates whether autophagy participates in BPA-triggered IR so far. In our preliminary studies we found that treatment of HepG2 cells with BPA suppressed autophagic activity, stimulated inflammatory response and induced IR. Sulforaphane, an isothiocyanate obtained from cruciferous vegetables, effectively attenuated these effects of BPA. In this proposed research, we will for the first time confirm the role of autophagy in BPA-induced IR and its regulatory mechanism by using both in vitro and in vivo mouse models. It has been reported that endoplasmic reticulum (ER) stress and mitochondrial dysfunction induce inflammatory response, so we will evaluate the underling mechanism of autophagy-mediated BPA-induced IR through ER stress and mitochondrial dysfunction. Furthermore, this research will determine the function of autophagy in the protective effects of sulforaphane against BPA-induced IR. Findings from this research will provide new insights into the elucidation of the molecular mechanisms by which BPA causes IR and its target intervention.

研究显示广泛存在并可经多种途径进入机体的双酚A（BPA）与胰岛素抵抗（insulin resistance, IR）和糖尿病的发生发展密切相关。近年来自噬与胰岛素抵抗及炎症反应的关系受到关注，但在环境内分泌干扰物BPA所致IR过程中自噬是否发挥及如何发挥作用尚未见报道。本课题组在前期研究中发现在BPA诱导的IR细胞模型和动物模型中，自噬活性降低，炎症反应升高，同时发现植物化学物莱菔硫烷可逆转上述变化。本课题拟在此基础上运用体内、体外模型，从整体、器官、细胞、分子等层次探讨自噬在BPA诱导的胰岛素抵抗及莱菔硫烷改善BPA致胰岛素抵抗过程中的作用，并聚焦于自噬对胰岛素抵抗模型内质网应激、线粒体损伤及炎症的影响及调控机制。本研究将为深入探讨环境内分泌干扰物BPA及同类物质诱导胰岛素抵抗的分子机制提供新的研究策略，并为营养干预BPA致代谢性疾病提供重要的科学依据。

研究显示广泛存在并可经多种途径进入机体的双酚A（BPA）与胰岛素抵抗（insulin resistance, IR）和糖尿病的发生发展密切相关。近年来自噬与胰岛素抵抗及炎症反应的关系受到关注，但在环境内分泌干扰物BPA所致IR过程中自噬是否发挥及如何发挥作用尚未见报道。本课题运用体内、体外模型，从整体、器官、细胞、分子等层次探讨自噬在BPA诱导的胰岛素抵抗及莱菔硫烷改善BPA致胰岛素抵抗过程中的作用，并聚焦于自噬对内质网应激及炎症信号通路的影响及相互间的调控机制。本研究发现在BPA诱导的胰岛素抵抗模型中，自噬被抑制；激活自噬后可改善胰岛素抵抗并抑制炎症信号通路，但对内质网应激无显著影响；同时，在胰岛素抵抗模型中，抑制内质网应激可增强自噬、抑制炎症信号通路。研究结果表明了内质网应激/自噬/炎症信号通路在调控BPA诱导胰岛素抵抗过程中的关键作用及其机制。并在此基础上进行了莱菔硫烷对BPA诱导胰岛素抵抗的实验干预研究。本项目在领域内获得了重要的研究结果，为深入探索BPA诱导胰岛素抵抗的调控机制和其关键靶点，从而为胰岛素抵抗的营养干预研究提供了重要的科学依据，具有重要的科学意义。