Elevation of fatty acid desaturase 2 in esophageal adenocarcinoma increases polyunsaturated lipids and may exacerbate bile acid-induced DNA damage
- Author(s)
- Molendijk, J; Kolka, CM; Cairns, H; Brosda, S; Mohamed, A; Shah, AK; Brown, I; Hodson, MP; Hennessy, T; Liu, G; Stoll, T; Richards, RS; Gartside, M; Patel, K; Clemons, NJ; Phillips, WA; Barbour, A; Westerhuis, JA; Hill, MM;
- Details
- Publication Year 2022-05,Volume 12,Issue #5,Page e810
- Journal Title
- Clinical and Translational Medicine
- Publication Type
- Research article
- Abstract
- BACKGROUND: The risk of esophageal adenocarcinoma (EAC) is associated with gastro-esophageal reflux disease (GERD) and obesity. Lipid metabolism-targeted therapies decrease the risk of progressing from Barrett's esophagus (BE) to EAC, but the precise lipid metabolic changes and their roles in genotoxicity during EAC development are yet to be established. METHODS: Esophageal biopsies from the normal epithelium (NE), BE, and EAC, were analyzed using concurrent lipidomics and proteomics (n = 30) followed by orthogonal validation on independent samples using RNAseq transcriptomics (n = 22) and immunohistochemistry (IHC, n = 80). The EAC cell line FLO-1 was treated with FADS2 selective inhibitor SC26196, and/or bile acid cocktail, followed by immunofluorescence staining for gammaH2AX. RESULTS: Metabolism-focused Reactome analysis of the proteomics data revealed enrichment of fatty acid metabolism, ketone body metabolism, and biosynthesis of specialized pro-resolving mediators in EAC pathogenesis. Lipidomics revealed progressive alterations (NE-BE-EAC) in glycerophospholipid synthesis with decreasing triglycerides and increasing phosphatidylcholine and phosphatidylethanolamine, and sphingolipid synthesis with decreasing dihydroceramide and increasing ceramides. Furthermore, a progressive increase in lipids with C20 fatty acids and polyunsaturated lipids with >/=4 double bonds were also observed. Integration with transcriptome data identified candidate enzymes for IHC validation: Delta4-Desaturase, Sphingolipid 1 (DEGS1) which desaturates dihydroceramide to ceramide, and Delta5 and Delta6-Desaturases (fatty acid desaturases, FADS1 and FADS2), responsible for polyunsaturation. All three enzymes showed significant increases from BE through dysplasia to EAC, but transcript levels of DEGS1 were decreased suggesting post-translational regulation. Finally, the FADS2 selective inhibitor SC26196 significantly reduced polyunsaturated lipids with three and four double bonds and reduced bile acid-induced DNA double-strand breaks in FLO-1 cells in vitro. CONCLUSIONS: Integrated multiomics revealed sphingolipid and phospholipid metabolism rewiring during EAC development. FADS2 inhibition and reduction of the high polyunsaturated lipids effectively protected EAC cells from bile acid-induced DNA damage in vitro, potentially through reduced lipid peroxidation.
- Keywords
- *Adenocarcinoma/genetics/metabolism/pathology; *Barrett Esophagus/genetics/metabolism/pathology; Bile Acids and Salts; DNA Damage/genetics; Esophageal Neoplasms; Fatty Acid Desaturases/genetics/metabolism; Fatty Acids; Humans; Sphingolipids; Barrett's esophagus; Fads2; esophageal adenocarcinoma; lipid desaturation; lipid metabolism
- Department(s)
- Laboratory Research
- PubMed ID
- 35560527
- Publisher's Version
- https://doi.org/10.1002/ctm2.810
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-02-07 03:35:31
Last Modified: 2025-02-07 03:38:02