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Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability

Title
Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability
Authors
Kim Y.-R.Volpert G.Shin K.-O.Kim S.-Y.Shin S.-H.Lee Y.Sung S.H.Lee Y.-M.Ahn J.-H.Pewzner-Jung Y.Park W.-J.Futerman A.H.Park J.-W.
Ewha Authors
안정혁박주원
SCOPUS Author ID
안정혁scopus; 박주원scopus
Issue Date
2017
Journal Title
Journal of Cellular and Molecular Medicine
ISSN
1582-1838JCR Link
Citation
vol. 21, no. 12, pp. 3565 - 3578
Keywords
acyl chainsceramidedextran sodium sulphateinflammatory bowel diseasesphingolipid
Publisher
Blackwell Publishing Inc.
Indexed
SCOPUS WOS scopus
Abstract
Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long-chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very-long acyl chain ceramides with concomitant increase of long chain bases and C16-ceramides, were more susceptible to dextran sodium sulphate-induced colitis, and their survival rate was markedly decreased compared with that of wild-type littermates. Using mixed bone-marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule-A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. In vitro experiments using Caco-2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2-knockdown via CRISPR-Cas9 technology impaired barrier function. In vivo myriocin administration, which normalized long-chain bases and C16-ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC-dextran levels, indicating that altered SLs including deficiency of very-long-chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
DOI
10.1111/jcmm.13267
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의과대학 > 의학과 > Journal papers
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