Disturbance of Fatty Acid Desaturation Mediated by FADS2 in Mesenteric Adipocytes Contributes to Chronic Inflammation of Crohn's Disease
- 1 November 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Crohn's and Colitis
- Vol. 14 (11), 1581-1599
- https://doi.org/10.1093/ecco-jcc/jjaa086
Abstract
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.Funding Information
- National Natural Science Foundation of China (81670471, 81770556, 81570500)
- Jiangsu Provincial Medical Youth Talent (QNRC2016900)
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