PPAR-γ介导的物质代谢紊乱在脂肪肝合并急性胰腺炎中的分子机制研究

Hepatic steatoisis is one of independent risk factors of acute pancreatitis, however, its mechanism is still unclear. Our previous study has demonstrated that patients of acute pancreatitis with hepatic steatoisis could obviously depress AAT in serum, meanwhile severely aggravate the AP. What’s more, the PPARγ, a gene about material energy metabolism, and its downstream genes are up-regulated in APEL patients, while down regulated after pancreatitis. The mechanism of material energy metabolism is one of the hot spots for research in aspect of promotion of inflammation, however its mechanism is not clear. We used RNA-seq technology, through the enrichment of GO and KEGG channel, to analysis the transcriptomics. And we found that the PPARγ of JAK-STAT signal channel, insulin resistance and its down stream effective pathway can improve dramatically in rats models. Since we have already got the clues of PPARγ signal pathway, now whether PPARγ can effect the pancreatitis by relative inflammation signal pathway is a riddle for us to explore. In this project, we try to explore the mechanism of PPAR-γmediated metabolic disorders in hepatic adipose infiltration with acute pancreatitis both in vitro and in vivo. The findings from this study will help to reveal the mechanism and provide scientific evidences for the development of novel approaches about treatment of hepatic steatosis with acute pancreatitis.

脂肪肝作为急性胰腺炎的独立危险因素之一，其加重胰腺炎的机制尚不清楚。我们前期研究证实胰腺炎合并脂肪肝的患者血清AAT含量显著下降，且明显加重胰腺炎严重程度，同时物质能量代谢基因PPARγ及其相关基因在脂肪肝大鼠表达上调，而发生胰腺炎后该基因显著下调。物质能量代谢在脂肪肝患者促进炎症方面的作用是目前研究的热点之一，然而其机制仍不清楚。我们利用高通量测序中技术（RNA-seq），通过GO及KEGG通路富集分析转录组学发现PPARγ通路及其作用的JAK-STAT、胰岛素抵抗等信号通路在脂肪肝胰腺炎大鼠富集程度明显上升。物质能量代谢基因PPARγ是否通过相关炎症通路加重胰腺炎？本课题将在前期研究的基础之上，通过转录组学、蛋白组学、基因敲除以及基因转染等分子生物学技术，从体内、体外研究探讨PPARγ相关基因在脂肪肝患者加重急性胰腺炎的分子机制，为脂肪肝合并胰腺炎的治疗提供理论依据。

脂肪肝作为急性胰腺炎的独立危险因素之一，其加重胰腺炎的机制尚不清楚。既往研究显示PPAR-γ通路参与脂肪肝的发生中，但是PPAR-γ通路是否参与脂肪肝伴急性胰腺炎的发生亦不清楚。在本项目中，我们的主要研究内容为PPAR-γ基因在脂肪肝伴急性胰腺炎中的作用及其通路相关基因的筛选、急性胰腺炎伴脂肪肝发生机制的RNA-seq研究、血清甘油三酯在评估急性胰腺炎预后的作用、ALKBH3在肝癌侵袭与转移中的作用、CpG岛甲基化与肝癌预后的关系、GSDMD介导的巨噬细胞焦亡在急性胰腺炎中的作用研究。本项目已经取得多项成果，已有五篇SCI论文发表，未发表的研究已经取得重要进展：包括发现GSDMD介导的巨噬细胞焦亡在急性胰腺炎中激活放大了炎症反应，并且抑制GSDMD蛋白对胰腺炎症具有减轻作用。本项目研究成果对急性胰腺炎的临床治疗具有指导作用、对未来急性胰腺炎药物治疗新靶点的研究临床转化具有重要价值。