肥胖通过影响线粒体膜通道增加急性坏死性胰腺炎风险的机制探讨

Obesity is a definite risk factor for such a disease. However, it is unclear how obesity increases the risk of developing acute necrotizing pancreatitis (ANP). Previous studies showed that the development of ANP depends on the ratio of necrosis and apoptosis of pancreatic acinar cell which is influenced by the mitochondrial permeability. It has been found that several adipokines are correlated with increased mitochondrial permeability in skeletal muscle cells, cardiomyocytes and adipocytes. Therefore, it can be concluded that, obese alteres the level of aipokines which may increase the mitochondrial permeability. Then the increase the mitochondrial permeability decreases the ATP production and disturbed the ratio between necrosis and apoptosis of pancreatic acinar cell and finally lead to ANP. In this study, to investigate whether obesity increases the risk of ANP through increasing the mitochondrial permeability, the mitochondrial permeability of pancreatic acinar cells are compared between obese and lean rats after ANP were induced. To identify the specific adipokin which increases the mitochondrial permeability, pancreatic acina cells are pretreated with different types of adipokines and the ratio between apoptosis and necrosis are compared among different groups after AP is induced by CCK. To clarify the usfuness of mitochondrial protection in treating obese related ANP, the permeability transision pores are blocked in obese mice and adipokines pretreated pancreatic acina cell and the severity between intervention and control groups are compared. This study may not only provide us an additional explanation for the increased incidence of ANP in obese patients, but also a potential target for the clinical intervention in preventing the development of ANP.

同样受到胰腺炎病因刺激，为何肥胖患者易进展为急性坏死性胰腺炎(acute necrotizing pancreatitis, ANP)？相关机制的假说集中于脂肪因子放大炎症的即时效应，尚无研究关注其长期紊乱对胰腺细胞的影响。研究显示线粒体膜通透性增加是胰腺炎病程中胰腺细胞坏死的重要原因，而脂肪因子长时间作用可激活JAK2/STAT3信号影响多种细胞线粒体膜通透性。我们发现肥胖小鼠发生急性胰腺炎时易进展为ANP，且胰腺线粒体肿胀程度显著高于正常体重小鼠。以上结果提示肥胖可能通过脂肪因子激活JAK2/STAT3增加线粒体膜通道敏感性，增加胰腺细胞受损后的坏死风险。本课题拟比较肥胖与正常体重小鼠发生ANP时胰腺细胞线粒体膜通透性的差异；比较不同脂肪因子长时间处理后胰腺线粒体膜通透性的改变；比较阻断JAK2/STAT3信号或线粒体膜通道在肥胖相关ANP中的治疗价值。为改善ANP的预后提供干预途径。

肥胖患者容易进展为急性坏死性胰腺炎，研究报道肥胖患者体内脂肪组织会分泌大量脂肪因子，并且线粒体的功能会出现紊乱。本课题从脂肪因子和线粒体入手，研究肥胖加重胰腺炎的相关机制。我们对课题组前期纳入的胰腺炎患者血清中的多种脂肪因子进行检测，并与临床常用的APACHE- II评分对比预测胰腺炎患者发生持续性器官衰竭的准确性。结果显示血清抵抗素和瘦素水平可以较好地预测持续性器官衰竭。我们成功建立肥胖小鼠模型，之后诱导胰腺炎，结果发现肥胖小鼠发生胰腺炎时线粒体肿胀明显，嵴突消失，并且坏死性凋亡标志RIP3表达增加，提示线粒体功能紊乱。同时我们对咖啡因与肥胖胰腺炎的关系进行研究，结果表明咖啡因可以缓解肥胖小鼠胰腺炎的炎症程度。本研究从全新的角度探索肥胖加重胰腺炎的机制，并为今后肥胖并发胰腺炎的防治提供新思路。

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