期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 350, 期 -, 页码 -出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2021.109689
关键词
Eicosanoids; Dehydrogenase; Fatty acid/metabolism; Fatty acid/oxidation; Mass spectrometry; oxoETE; KETE; Prostaglandin reductase
资金
- National Institutes of Health [P30ES013508, K22ES26235, UL1TR000005, R21AI12207]
- National Institutes of Health (NIH) [CA148629, ES029518, ES028949, CA238061, AG069740, ES032522]
- Na-tional Science Foundation (NSF) [NSF-1841811]
- Abraham A. Mitchell Distinguished Investigator Fund
- Mitchell Cancer Institute Molecular & Metabolic Oncology Program Develop fund
This study investigated the metabolism of oxo-fatty acid products and found that mono-saturated oxo-fatty acids maintained their electrophilicity, while a secondary saturation resulted in a loss of electrophilicity. Prostaglandin reductase 1 (PTGR1) was found to play a critical role in the formation of mono-saturated metabolites of 15-oxoETE and 17-oxoDHA. Overexpression of PTGR1 increased the rate and total amount of oxo-fatty acid saturation in A549 cells.
Metabolism of polyunsaturated fatty acids results in the formation of hydroxylated fatty acids that can be further oxidized by dehydrogenases, often resulting in the formation of electrophilic, alpha,beta-unsaturated ketone containing fatty acids. As electrophiles are associated with redox signaling, we sought to investigate the metabolism of the oxo-fatty acid products in relation to their double bond architecture. Using an untargeted liquid chromatography mass spectrometry approach, we identified mono-and di-saturated products of the arachidonic acid-derived 11-oxoeicosatetraenoic acid (11-oxoETE) and mono-saturated metabolites of 15-oxoETE and docosahexaenoic acid-derived 17-oxodocosahexaenoinc acid (17-oxoDHA) in both human A549 lung carcinoma and umbilical vein endothelial cells. Notably, mono-saturated oxo-fatty acids maintained their electrophilicity as determined by nucleophilic conjugation to glutathione while a second saturation of 11-oxoETE resulted in a loss of electrophilicity. These results would suggest that prostaglandin reductase 1 (PTGR1), known only for its reduction of the alpha,beta-unsaturated double bond, was not responsible for the saturation of oxo-fatty acids at alternative double bonds. Surprisingly, knockdown of PTGR1 expression by shRNA confirmed its participation in the formation of 15-oxoETE and 17-oxoDHA mono-saturated metabolites. Furthermore, overexpression of PTGR1 in A549 cells increased the rate and total amount of oxo-fatty acid saturation. These findings will further facilitate the study of electrophilic fatty acid metabolism and signaling in the context of inflammatory diseases and cancer where they have been shown to have anti-inflammatory and anti-proliferative signaling properties.
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