肠系膜脂肪细胞功能障碍在克罗恩病中的意义及HIF通路的调节作用

Mesenteric adipose tissue is a unique feature of Crohn's disease (CD), the role played by mesenteric adipose tissue in the pathogenesis of CD has recently been recognized. It is currently accepted that mesenteric adipose fat is important in disease development and progression of CD. The crosstalk between mesentetic adipose tissue and bowel is mainly through the secretion of adipokines and cytokines from mesenteric adipocyte although the detailed information remains unknown. Work of our group have indicated that the hypertrophic mesenteric adipose tissue which is found in patients with CD, is associated with disease process, disease activity, and disease recurrence of CD. In addition, we found that improvement of the mesenteric function of adipocyte is related to attenuated animal colitis. We proposed this project based on our previous work, we aimed to explore the underlying mechanisms metabolic disorders and pattern recognition receptors abnormal of mesenteric adipocyte, and we hypothesized that HIF pathway may be implicated in the disorders of mesenteric adipocyte. The histopathology, molecular biology and molecular immunology would be used in this study. Our study would provide data to understand the pathogenesis of CD and suggest a novel target for the management of CD.

肠系膜脂肪组织结构及功能的异常与肠道慢性炎症相互作用，参与了克罗恩病(CD)的疾病进程。本课题组既往研究表明，CD肠系膜脂肪细胞存在结构及功能异常，肠系膜脂肪增生与CD疾病严重程度及术后复发显著相关。改善肠系膜脂肪细胞的功能明显减轻CD模型小鼠的肠道炎症。本课题在前期研究的基础之上，运用分子生物学及分子免疫学等技术，从肠系膜脂肪细胞脂代谢障碍及模式识别受体异常的角度探讨CD肠系膜脂肪细胞功能障碍的机制，并以缺氧诱导因子(HIF)通路为切入点，探寻肠系膜脂肪组织炎症发生的根源以及可能的调控机制，以期揭示肠系膜脂肪细胞功能障碍在CD肠道炎症发生及发展中的作用及机制，为阐释 CD 病理生理提供理论依据，为CD的防治提供新的靶点。

肠系膜脂肪组织结构及功能的异常与肠道慢性炎症相互作用，参与了克罗恩病(CD)的疾病进程。本课题组既往研究表明，CD肠系膜脂肪细胞存在结构及功能异常，肠系膜脂肪增生与CD疾病严重程度及术后复发显著相关。改善肠系膜脂肪细胞的功能明显减轻CD模型小鼠的肠道炎症。本课题在前期研究的基础之上，运用分子生物学及分子免疫学等技术，从肠系膜脂肪细胞脂代谢障碍及模式识别受体异常的角度探讨CD肠系膜脂肪细胞功能障碍的机制，探寻肠系膜脂肪组织炎症发生的根源以及可能的调控机制，以期揭示肠系膜脂肪细胞功能障碍在CD肠道炎症发生及发展中的作用及机制。.本课题研究表明，CD患者病变部位肠系膜脂肪细胞代谢障碍、脂肪组织促炎性M1型巨噬细胞浸润增多。CD 肠系膜脂肪组织慢性炎症与肠系膜代谢模式显著改变相关，肠系膜不饱和脂肪酸合成的代谢途径障碍导致巨噬细胞聚集和脂肪组织炎症。研究发现脂肪细胞的从TLRs和 NODs通路异常激活，相应的下游通路也出现紊乱，并导致促炎因子的表达明显增加。进一步研究发现HIF通路参与了CD肠系膜脂肪细胞的增殖和代谢障碍，调控HIF通路能够减少肠系膜脂肪细胞的凋亡和自噬，揭示了HIF通路促进肠系膜炎症反应的机制。深入研究发现，作为调节不饱和脂肪酸的关键因子FADS2在CD肠系膜脂肪中显著降低，可能是肠系膜脂肪细胞脂肪酸代谢障碍及促炎反应的诱因。外源性干预限速酶FADS2的活性可以改善肠系膜脂肪炎症及诱导巨噬细胞向M2极化，从而改善肠道炎症。本课题研究结果表明肠系膜内脂肪细胞代谢紊乱促进了肠系膜局部及肠道炎症，调节脂肪细胞的脂代谢能够有效减轻肠系膜脂肪组织炎症及肠道炎症。本项目研究结果为阐释 CD 病理生理提供理论依据、为CD的防治提供新的靶点。