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Schäfer, A. ; Neschen, S. ; Kahle-Stephan, M. ; Sarioglu, H. ; Gaisbauer, T. ; Imhof, A.* ; Adamski, J. ; Hauck, S.M. ; Ueffing, M.

The epoxyeicosatrienoic acid pathway enhances hepatic insulin signaling and is repressed in insulin-resistant mouse liver.

Mol. Cell. Proteomics 14, 2764-2774 (2015)
Verlagsversion DOI PMC
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
While it is widely accepted that ectopic lipid accumulation in the liver is associated with hepatic insulin resistance, the underlying molecular mechanisms have not been well characterized. Here we employed time resolved quantitative proteomic profiling of mice fed a high fat diet to determine which pathways were affected during the transition of the liver to an insulin-resistant state. We identified several metabolic pathways underlying altered protein expression. In order to test the functional impact of a critical subset of these alterations, we focused on the epoxyeicosatrienoic acid (EET) eicosanoid pathway, whose deregulation coincided with the onset of hepatic insulin resistance. These results suggested that EETs may be positive modulators of hepatic insulin signaling. Analyzing EET activity in primary hepatocytes, we found that EETs enhance insulin signaling on the level of Akt. In contrast, EETs did not influence insulin receptor or insulin receptor substrate-1 phosphorylation. This effect was mediated through the eicosanoids, as overexpression of the deregulated enzymes in absence of arachidonic acid had no impact on insulin signaling. The stimulation of insulin signaling by EETs and depression of the pathway in insulin resistant liver suggest a likely role in hepatic insulin resistance. Our findings support therapeutic potential for inhibiting EET degradation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Absolute Quantification ; Eicosanoids ; Ephx2 ; High Fat Diet ; Insulin Resistance ; Label-free Quantification ; Selected Reaction Monitoring ; Signal Transduction*
ISSN (print) / ISBN 1535-9476
e-ISSN 1535-9484
Zeitschrift Molecular and Cellular Proteomics
Quellenangaben Band: 14, Heft: 10, Seiten: 2764-2774 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CF Metabolomics & Proteomics (CF-MPC)
Molekulare Endokrinologie und Metabolismus (MEM)
Institute of Experimental Genetics (IEG)