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Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis

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Title: Epoxygenase inactivation exacerbates diet and aging-associated metabolic dysfunction resulting from impaired adipogenesis
Authors: Olona, A
Terra, X
Ko, JH
Grau-Bove, C
Pinent, M
Ardevol, A
Garcia Diaz, A
Moreno-Moral, A
Edin, M
Bishop-Bailey, D
Zeldin, DC
Aitman, TJ
Petretto, E
Blay, M
Behmoaras, JV
Item Type: Journal Article
Abstract: Objective : W hen molecular drivers of healthy adipogenesis are perturbed, this can cause hepatic steatosis . The role of arachidonic acid (AA) and its downstream enzymatic cascades such as cyclooxygenase in adipogenesis is well established while the exact contribution of P450 epoxygenase pathway remain to be established. Enzymes belonging to this pathway are mainly encoded by the CYP2J locus but the latter shows extensive allelic expansion in mice , an obstacle for adipogenesis -related studies . The human CYP2J locus cont ains a single gene (CYP2J2) whereas mice and rats have 8 and 3 paralogues, respectively. Methods and results : We took advantage of the simpler genetic architecture of the Cyp2j locus in the rat and generated a Cyp2j4 (orthologue of human CYP2J2 ) knockout rat . We used Cyp2j4 - /- rats in two models of metabolic dysfunction: physiological aging and cafeteria diet (CAF). The phenotyping of Cyp2j4 - /- rats under CAF was integrated with proteomics (LC - MS/MS ) and lipidomics (LC -MS) analyses in the liver and the adi pose tissue. We report that Cyp2j4 deletion causes adipocyte dysfunction under metabolic challenges. This is characterised by (i) down- regulation of white adipose tissue (WAT) PPARγ and C/EBPα , (ii) adipocyte hypertrophy (iii) extracellular matrix remodelling and (iv) alternative usage of AA pathway . Specifically, in Cyp2j4 -/- rats treated with a cafeteria diet, the dysfunctional adipogenesis is accompanied by exacerbated weight gain, hepatic lipid ac cumulation and dysregulated gluconeogenesis . Conclusion : These results suggest that AA epoxygenases are essential regulat ors of healthy adipogenesis. Our results uncover their synergistic role in fine -tuning AA pathway in obesity -mediated hepatic steatosis.
Issue Date: 1-May-2018
Date of Acceptance: 5-Mar-2018
URI: http://hdl.handle.net/10044/1/57854
DOI: https://dx.doi.org/10.1016/j.molmet.2018.03.003
ISSN: 2212-8778
Publisher: Elsevier
Start Page: 18
End Page: 32
Journal / Book Title: Molecular Metabolism
Volume: 11
Copyright Statement: © 2018 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
Sponsor/Funder: Kidney Research UK
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: RP9/2013
MR/M004716/1
MR/N01121X/1
Keywords: Adipogenesis
Aging
Arachidonic acid
Cafeteria diet
Cytochrome P450 2j4
Steatosis
Publication Status: Published
Online Publication Date: 2018-03-09
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine



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