高密度脂蛋白通过SR-B1保护急性胰腺炎腺泡细胞损伤的作用及机制研究

Recent researches have indicated that abnormal lipid metabolism is closely associated with pancreatic acinar cell damage and the progression of acute pancreatitis(AP). Besides triglycerides, high-density lipoprotein (HDL) also has important effects on the process of AP. The Anti-inflammatory effect of HDL is closely associated with its compositions and functions and the changes of HDL compositions or functions may cause anti-inflammatory effects weakened or lost in acute inflammation..Our previous study has found that (1) Plasma HDL level is an independent risk factor of severe AP (2) HDL can significantly reduce the AP acinar cell damage in mice (3) Acinar cells express HDL receptor SR-B1 and the acinar cell damage in SR-B1 knockout mice is significantly more severe than in wild type mice. Therefore, we assume that the changes of HDL compositions and functions play an important role in the process of AP progression; HDL can protect AP acinar cells via SR-B1 pathway. In this subject, (1) we will confirm the change of plasma HDL compositions and functions in AP patients and analyze its correlations with disease severity and prognosis. (2) In vivo or in vitro AP model, we will knockout or transgenic the expression of apoA-I which is the main functional protein of HDL to confirm its effect on AP, what’s more, the protective effect of different compositions and functions of HDL on the acinar cells will be verified. (3) we will Investigate the molecular mechanism of the protect effects of HDL in acinar cells via SR - B1 pathway. The results of the subject will further enrich the pathogenesis of AP and provide the potential therapeutic targets for AP.

研究表明脂质代谢异常与腺泡细胞损伤、急性胰腺炎（AP）的进展关系密切，除甘油三酯外，高密度脂蛋白（HDL）也对AP具有重要影响；HDL抗炎作用与组分、功能密切相关，急性炎症时HDL组分、功能改变，其抗炎作用减弱或丧失。我们前期发现①HDL水平降低是重症胰腺炎独立危险因素；②HDL显著减轻AP小鼠腺泡细胞损伤；③腺泡细胞表达HDL受体SR-B1且SR-B1缺陷小鼠AP腺泡细胞损伤高于野生型小鼠。我们假设：HDL组分及功能改变在AP进展中具有重要作用；HDL通过SR-B1介导对腺泡细胞的保护。本课题将①确认AP患者HDL组分及功能改变，分析与疾病严重程度和预后的关系；②在体内体外AP模型，验证HDL主要功能蛋白apoA-I缺失或高表达对AP的作用，及不同组分功能HDL对腺泡细胞的保护作用；③验证HDL通过SR-B1保护腺泡细胞的分子机制。研究结果将进一步丰富AP的发病机理，提供可能的防治靶点。

研究表明，脂质代谢异常与腺泡细胞损伤、急性胰腺炎（AP）的进展关系密切，除甘油三酯外，高密度脂蛋白（HDL）也对AP具有重要影响；HDL抗炎作用与组分、功能密切相关，急性炎症时HDL组分、功能改变，其抗炎作用减弱或丧失。本项目发现①正常功能HDL对AP腺泡细胞损伤具有保护作用；②HDL主要功能蛋白apoA-Ⅰ缺失加剧不同小鼠AP模型时胰腺炎症程度；③HDL可能通过抑制NLRP3炎症小体激活以及下游相关通路减轻AP腺泡细胞损伤；④AP患者血浆HDL组分和功能发生改变，并且与AP患者病情严重程度具有相关性。本项目研究结果将进一步丰富AP的发病机理，为AP临床提供可能的防治靶点。