title: The Epoxyeicosatrienoic Acid Pathway Enhances Hepatic Insulin Signaling and is Repressed in Insulin-Resistant Mouse Liver.
abstract: Although 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.
authors.affiliation: From the ‡Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg; §German Center for Diabetes Research (DZD), Neuherberg, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Schäfer
authors.affiliation: §German Center for Diabetes Research (DZD), Neuherberg, Germany; ¶Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg;
authors.forename: Susanne
authors.initials: S
authors.lastname: Neschen
authors.affiliation: §German Center for Diabetes Research (DZD), Neuherberg, Germany; ¶Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg;
authors.forename: Melanie
authors.initials: M
authors.lastname: Kahle
authors.affiliation: From the ‡Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg; §German Center for Diabetes Research (DZD), Neuherberg, Germany;
authors.forename: Hakan
authors.initials: H
authors.lastname: Sarioglu
authors.affiliation: §German Center for Diabetes Research (DZD), Neuherberg, Germany; ¶Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg;
authors.forename: Tobias
authors.initials: T
authors.lastname: Gaisbauer
authors.affiliation: ‖Munich Center of Integrated Protein Science, Adolf-Butenandt Institute, Ludwig Maximilians University of Munich, Germany, Schillerstraβe 44, 80336 Munich;
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.affiliation: §German Center for Diabetes Research (DZD), Neuherberg, Germany; ¶Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg; **Institute of Experimental Genetics, Technical University Munich, Freising-Weihenstephan, Germany;
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: From the ‡Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg; §German Center for Diabetes Research (DZD), Neuherberg, Germany; hauck@helmholtz-muenchen.de.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Hauck
authors.affiliation: From the ‡Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Germany, Ingolstädter Landstr.1 8674 Neuherberg; §German Center for Diabetes Research (DZD), Neuherberg, Germany; ‡‡Centre of Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Germany, Röntgenweg 11,72076 Tübingen.
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
mesh_terms: D000818:Animals; D002460:Cell Line; D059305:Diet, High-Fat; D015777:Eicosanoids / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D040901:Proteomics; D012450:Safflower Oil; D015398:Signal Transduction
chemical_list: D015777:Eicosanoids; D007328:Insulin; D012450:Safflower Oil