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Time-resolved phosphoproteomic analysis elucidates hepatic 11,12-Epoxyeicosatrienoic acid signaling pathways.
Prostaglandins Other Lipid Mediat. 146:106387 (2020)
Epoxyeicosatrienoic acids (EETs) are potent lipid mediators with well-established effects in vascular tissues. Recent studies indicated an emerging role of these eicosanoids in metabolic diseases and the EET signaling pathway was shown to be involved in hepatic insulin sensitivity. However, compared to vascular tissues, there is only limited knowledge about the underlying signaling pathways in the liver. Therefore, we employed an LC-MS/MS-based time-resolved phosphoproteomics approach to characterize 11,12-EET-mediated signaling events in the liver cell line Hepa 1-6.11,12-EET treatment resulted in the time-dependent regulation of phosphopeptides involved in processes as yet unknown to be affected by EETs, including RNA processing, splicing and translation regulation. Pathway analysis combined with western blot-based validation revealed enhanced AKT/mTOR/p70S6K signaling as demonstrated by increased acute phosphorylation of AKT (Ser473) and p70S6K (Thr389). In addition, 11,12-EET treatment led to differential regulation of phosphopeptides including important mediators of the DNA damage response and we observed a prolonged induction of the etoposide-induced DNA damage marker gamma H2AX in response to 11,12-EET.In summary, our findings extend current knowledge of 11,12-EET signaling events and emphasize the importance of the AKT/mTOR/p70S6K pathway in hepatic 11,12-EET signaling. Based on the results presented in this study, we furthermore propose a novel role of EET signaling in the regulation of the DNA damage response.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Lipid Signaling ; Akt/mtor/p70s6k Pathway ; Eicosanoids ; Lc-ms/ms ; Tio2; Soluble Epoxide Hydrolase; Hyperpolarizing Factor Edhf; Light-chain Phosphatase; Epoxyeicosatrienoic Acids; Smooth-muscle; Phosphopeptide Enrichment; Substrate-specificity; Glucose-homeostasis; 14,15-eet Binding; Arachidonic-acid
ISSN (print) / ISBN
1098-8823
e-ISSN
2212-196X
Quellenangaben
Volume: 146,
Article Number: 106387
Publisher
Elsevier
Publishing Place
Ste 800, 230 Park Ave, New York, Ny 10169 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
CF Metabolomics & Proteomics (CF-MPC)
Molekulare Endokrinologie und Metabolismus (MEM)
Molekulare Endokrinologie und Metabolismus (MEM)