Lipidomic Profiling Reveals Soluble Epoxide Hydrolase As a Therapeutic Target of Obesity‐induced Colonic Inflammation

Abstract

Obesity is associated with enhanced colonic inflammation, which is a major risk factor of colorectal cancer. Considering the obesity epidemic in United States, there is an urgent need to identify novel therapeutic targets for obesity‐induced colonic inflammation. Eicosanoids are endogenous lipid signaling molecules involved in regulating inflammation and immune responses. Using a LC‐MS/MS‐based lipidomics approach, we found that obesity‐induced colonic inflammation is associated with increased expression of soluble epoxide hydrolase (sEH) and its eicosanoid metabolites, termed fatty acid diols, in colon tissue. To study the functional role of sEH, we treated mice with sEH inhibitors, TPPU or t‐TUCB, in high fat diet (HFD)‐induce obesity model, and found that pharmacological inhibition of sEH attenuated obesity‐induced colonic inflammation. Administration of sEH inhibitors diminished obesity‐induced infiltration of immune cells and expressions of pro‐inflammatory cytokines in colon tissue. Furthermore, we examined the sEH−/− mice in obesity model, and found genetic ablation of sEH reduced colonic concentrations of fatty acid diols and decreased the expressions of pro‐inflammatory cytokines. Finally, HFD treatment increased expression of phosphorylated GSK3β in colon tissue, while such effect was attenuated in sEH−/− mice, or by treatment with sEH inhibitors, suggesting that pharmacological inhibition and genetic ablation of sEH attenuated HFD‐induced activation of Wnt signaling in colon. Together, these results support that sEH could be a novel therapeutic target for obesity‐induced colonic inflammation and associated diseases.Support or Funding InformationThis work was supported by USDA NIFA grants 2016‐67017‐24423 and 2014‐67017‐21762, NIEHS grant R01 ES002710 and NIEHS Superfund Research Program P42 ES004699, and National Natural Science Foundation of China (NSFC) grants 81702832, 81672938 and 81470588.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.