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Rahm, M. ; Merl-Pham, J. ; Adamski, J. ; Hauck, S.M.

Time-resolved phosphoproteomic analysis elucidates hepatic 11,12-Epoxyeicosatrienoic acid signaling pathways.

Prostaglandins Other Lipid Mediat. 146:106387 (2020)
Postprint DOI
Open Access Green
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
Language english
Publication Year 2020
Prepublished in Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 1098-8823
e-ISSN 2212-196X
Journal Prostaglandins & Other Lipid Mediators
Quellenangaben Volume: 146, Issue: , Pages: , Article Number: 106387 Supplement: ,
Publisher Elsevier
Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa
Reviewing status Peer reviewed
Institute(s) CF Metabolomics & Proteomics (CF-MPC)
Molekulare Endokrinologie und Metabolismus (MEM)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30201 - Metabolic Health
Research field(s) Enabling and Novel Technologies

Genetics and Epidemiology
PSP Element(s) G-505700-001
A-630700-001
G-505600-003
DOI 10.1016/j.prostaglandins.2019.106387
WOS ID WOS:000510312800002
Scopus ID 85075202556
Erfassungsdatum 2019-11-29
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