CYP eicosanoid pathway mediates colon cancer‐promoting effects of dietary linoleic acid

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω‐6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recomme...

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Published in:The FASEB journal 2023-07, Vol.37 (7), p.e23009-n/a
Main Authors: Zhang, Jianan, Yang, Jun, Duval, Caroline, Edin, Matthew L., Williams, Andrea, Lei, Lei, Tu, Maolin, Pourmand, Elham, Song, Renhua, Graves, Joan P., DeGraff, Laura M., Wong, Justin J.‐L., Wang, Yige, Sun, Quancai, Sanidad, Katherine Z., Wong, Siu, Han, Yanhui, Zhang, Zhenyu, Lee, Kin Sing Stephen, Park, Yeonhwa, Xiao, Hang, Liu, Zhenhua, Decker, Eric A., Cui, Wei, Zeldin, Darryl C., Zhang, Guodong
Format: Article
Language:English
Subjects:
Animals
Chromatography, Liquid
colon cancer
Colonic Neoplasms - etiology
Cytochrome P-450 Enzyme System - metabolism
cytochrome P450 monooxygenase
Diet
Eicosanoids
epoxy octadecenoic acids (EpOMEs)
Humans
linoleic acid
Linoleic Acid - metabolism
Linoleic Acid - pharmacology
lipidomics
Mice
precision health
Tandem Mass Spectrometry
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Summary:Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω‐6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer‐promoting effects. Using LC‐MS/MS‐based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer‐promoting effects of LA, since the LA‐rich diet fails to exacerbate colon cancer in CYP monooxygenase‐deficient mice. Finally, CYP monooxygenase mediates the pro‐cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota‐dependent mechanisms. Overall, these results support that CYP monooxygenase‐mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects. CYP monooxygenase‐mediated conversion of LA to EpOMEs contributes to the colon cancer‐enhancing effects of dietary LA. After a high intake of dietary LA, LA is metabolized by CYP monooxygenases (largely CYP2C and CYP2J isoforms), which are upregulated in colon tumors, leading to the formation of EpOMEs. EpOMEs have potent effects to induce colon tumorigenesis via gut microbiota‐dependent mechanisms. In contrast, DiHOMEs, which are downstream metabolites of EpOMEs, do not have such effects. Overall, these results support that CYP monooxygenase‐mediated conversion of LA to EpOMEs plays a critical role in mediating the colon cancer‐enhancing effects of dietary LA.
ISSN:0892-6638
1530-6860
1530-6860
DOI:10.1096/fj.202300786R