Disturbance of Fatty Acid Desaturation Mediated by FADS2 in Mesenteric Adipocytes Contributes to Chronic Inflammation of Crohn's Disease
Disturbance of Fatty Acid Desaturation Mediated by FADS2 in Mesenteric Adipocytes Contributes to Chronic Inflammation of Crohn's Disease
复制标题
肠系膜脂肪细胞中 FADS2 介导的脂肪酸去饱和紊乱导致克罗恩病的慢性炎症。
DOI：
10.1093/ecco-jcc/jjaa086
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发表时间：
2020-11-01
影响因子：
8
通讯作者：
Zhu, Weiming
中科院分区：
文献类型：
--
作者：
Liu, Ruiqing;Qiao, Shuaihua;Zhu, Weiming
背景和目的：本研究的目的是探讨克罗恩病[CD]中肠系膜脂肪细胞的代谢特征及其与局部炎症的关系。方法：通过对CD患者和对照组手术标本的肠系膜脂肪组织活检组织和原代培养的肠系膜脂肪细胞的代谢组学和功能分析，证明代谢功能障碍受脂肪酸去饱和酶-2[FADS2]的调节。利用慢病毒载体和腺相关病毒[AAV]分别在体外和体内高效表达FADS2。通过建立细胞共培养体系和FADS2-AAV处理的动物模型，研究肠系膜脂肪细胞与炎症反应之间的相互作用；利用3T3-L1细胞来阐明FADS2解除调控的机制。结果：我们观察到参与长链多不饱和脂肪酸(PUFAs)多步合成的代谢物水平发生了显著变化。气相色谱分析显示，通往n-6和n-3途径的去饱和通量受损，这与人肠系膜组织中FADS2活性降低有关。在手术标本中证实了FADS2在mRNA和蛋白水平的表达降低。恢复FADS2的表达，使n-3脂肪酸内源性转化为促溶解的脂质介质，导致促炎巨噬细胞的浸润明显减少，炎性细胞因子或脂肪因子的表达减弱。结论：这些结果表明，脂肪组织内脂肪酸去饱和度受损和脂质介质失衡是CD慢性炎症的原因之一。FADS2的治疗作用可能导致CD治疗的改进。
Background and Aims: The aim of this study was to investigate the metabolic profile of mesenteric adipocytes and the correlations between key metabolic changes and local inflammation in the context of Crohn's disease [CD].Methods: Metabolic dysfunction was shown to be regulated by fatty acid desaturase-2 [FADS2], through metabolomics and functional analyses of mesenteric adipose tissue biopsies and primary mesenteric adipocytes isolated from surgical specimens collected from CD patients and control subjects. FADS2 was overexpressed in vitro and in vivo using a lentiviral vector and an adeno-associated virus [AAV], respectively.The interaction between mesenteric adipocytes and inflammation responses was evaluated by establishing a cell coculture system and a FADS2-AAV treated animal model; 3T3-L1 cells were used to elucidate the mechanism underlying FADS2 deregulation.Results: We observed significant changes in the levels of metabolites involved in the multi-step synthesis of long-chain polyunsaturated fatty acids [PUFAs]. Gas chromatography analysis revealed impaired desaturation fluxes towards the n-6 and n-3 pathways, which are associated with reduced FADS2 activity in human mesentery tissue. Decreased FADS2 expression at both mRNA and protein levels was confirmed in surgical specimens. The restoration of FADS2 expression, which allows for the endogenous conversion of n-3 fatty acids into proresolving lipid mediators, resulted in a significant reduction in pro-inflammatory macrophage infiltration and attenuated expression of inflammatory cytokines or adipokines.Conclusions: These findings indicate that impaired fatty acid desaturation and lipid mediator imbalance within mesenteric adipose tissue contributes to chronic inflammation in CD. The therapeutic role of FADS2 may lead to improved CD treatment.