CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury.

Autor:	Leuillier M; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France., Duflot T; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France; Department of Pharmacology, Rouen University Hospital, F-76000 Rouen, France; Laboratory of Pharmacokinetics, Toxicology and Pharmacogenetics, Rouen University Hospital, F-76000 Rouen, France., Ménoret S; Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000 Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; Transgenesis Rat ImmunoPhenomic Platform, F-44000 Nantes, France., Messaoudi H; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France., Djerada Z; Department of Pharmacology, EA 3801, SFR CAP-santé, Reims University Hospital, F-51095 Reims Cedex, France., Groussard D; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France., Denis RGP; Unité de Biologie Fonctionnelle et Adaptative, Centre National la Recherche scientifique, Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France., Chevalier L; Normandie University, Unirouen, INSA Rouen, CNRS, Groupe de Physique des Matériaux-UMR6634, F-76000 Rouen, France., Karoui A; Normandie Univ, UNIROUEN, UNICAEN, ABTE, F-76000 Rouen, France., Panthu B; CarMeN Laboratory, INSERM, INRA, INSA, Université Claude Bernard Lyon 1, F-69600 Oullins, France., Thiébaut PA; Pathology Department, Rouen University Hospital, F-76000 Rouen, France., Schmitz-Afonso I; Normandie Univ, COBRA, UMR 6014 and FR 3038, Université de Rouen, INSA de Rouen, CNRS, IRCOF, F-76821, Mont-Saint-Aignan, Cedex, France., Nobis S; Animal Behavioral Platform (SCAC), HeRacLeS Inserm US51-CNRS UAR2026, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, F-76183 Rouen, France., Campart C; Animal Behavioral Platform (SCAC), HeRacLeS Inserm US51-CNRS UAR2026, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, F-76183 Rouen, France., Henry T; Animal Behavioral Platform (SCAC), HeRacLeS Inserm US51-CNRS UAR2026, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, F-76183 Rouen, France., Sautreuil C; Normandie Univ, UNIROUEN, INSERM U1245 and Rouen University Hospital, Department of Neonatal Paediatrics and Intensive Care, F-76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France., Luquet SH; Unité de Biologie Fonctionnelle et Adaptative, Centre National la Recherche scientifique, Université de Paris, BFA, UMR 8251, CNRS, F-75013 Paris, France., Beseme O; Univ. Lille, CHU Lille, Inserm, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000 Lille, France., Féliu C; Department of Pharmacology, EA 3801, SFR CAP-santé, Reims University Hospital, F-51095 Reims Cedex, France., Peyret H; Department of Pharmacology, EA 3801, SFR CAP-santé, Reims University Hospital, F-51095 Reims Cedex, France., Nicol L; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France., Henry JP; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France., Renet S; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France., Mulder P; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France., Wan D; Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA., Tesson L; Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000 Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; Transgenesis Rat ImmunoPhenomic Platform, F-44000 Nantes, France., Heslan JM; Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000 Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; GenoCellEdit Platform, F-44000 Nantes, France., Duché A; Institut Cochin, U1016 INSERM - UMR8104, CNRS - Université Paris Descartes, Genom'IC Platform, Bâtiment Gustave Roussy, F-75014 Paris, France., Jacques S; Institut Cochin, U1016 INSERM - UMR8104, CNRS - Université Paris Descartes, Genom'IC Platform, Bâtiment Gustave Roussy, F-75014 Paris, France., Ziegler F; Department of General Biochemistry, Rouen University Hospital, 76000 Rouen, France., Brunel V; Department of General Biochemistry, Rouen University Hospital, 76000 Rouen, France., Rautureau GJP; Centre de Résonance Magnétique Nucléaire à Très hauts Champs (FRE 2034, CNRS, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1), Université de Lyon, F-69100 Villeurbanne, France., Monteil C; Normandie Univ, UNIROUEN, UNICAEN, ABTE, F-76000 Rouen, France., do Rego JL; Animal Behavioral Platform (SCAC), HeRacLeS Inserm US51-CNRS UAR2026, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, F-76183 Rouen, France., do Rego JC; Animal Behavioral Platform (SCAC), HeRacLeS Inserm US51-CNRS UAR2026, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen Normandy, F-76183 Rouen, France., Afonso C; Normandie Univ, COBRA, UMR 6014 and FR 3038, Université de Rouen, INSA de Rouen, CNRS, IRCOF, F-76821, Mont-Saint-Aignan, Cedex, France., Hammock B; Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA., Madec AM; CarMeN Laboratory, INSERM, INRA, INSA, Université Claude Bernard Lyon 1, F-69600 Oullins, France., Pinet F; Institut Cochin, U1016 INSERM - UMR8104, CNRS - Université Paris Descartes, Genom'IC Platform, Bâtiment Gustave Roussy, F-75014 Paris, France., Richard V; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France; Department of Pharmacology, Rouen University Hospital, F-76000 Rouen, France., Anegon I; Nantes Université, CHU Nantes, Inserm, CNRS, SFR Santé, Inserm UMS 016, CNRS UMS 3556, F-44000 Nantes, France; Nantes Université, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, F-44000 Nantes, France; Transgenesis Rat ImmunoPhenomic Platform, F-44000 Nantes, France., Guignabert C; INSERM UMR_S 999, Hôpital Marie Lannelongue, F-92350 Le Plessis-Robinson, France; Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, F-94270 Le Kremlin-Bicêtre, France., Morisseau C; Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA 95616, USA., Bellien J; Normandy University, UniRouen, Inserm UMR1096 EnVI, FHU REMOD-VHF, F-76000 Rouen, France; Department of Pharmacology, Rouen University Hospital, F-76000 Rouen, France. Electronic address: jeremy.bellien@chu-rouen.fr.
Jazyk:	angličtina
Zdroj:	Journal of advanced research [J Adv Res] 2023 Jan; Vol. 43, pp. 163-174. Date of Electronic Publication: 2022 Mar 12.
DOI:	10.1016/j.jare.2022.03.004
Abstrakt:	Introduction: Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown. Objectives: This study aimed to assess in vivo the physiological role of sEH-P. Methods: CRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity. Results: The sEH-P KI rats has a decreased metabolism of lysophosphatidic acids to monoacyglycerols. KI rats grew almost normally but with less weight and fat mass gain while insulin sensitivity was increased compared to wild-type rats. This lean phenotype was more marked in males than in female KI rats and mainly due to decreased food consumption and enhanced energy expenditure. In fact, sEH-P KI rats had an increased lipolysis allowing to supply fatty acids as fuel to potentiate brown adipose thermogenesis under resting condition and upon cold exposure. The potentiation of thermogenesis was abolished when blocking PPARγ, a nuclear receptor activated by intracellular lysophosphatidic acids, but also when inhibiting simultaneously sEH-H, showing a functional interaction between the two domains. Furthermore, sEH-P KI rats fed a high-fat diet did not gain as much weight as the wild-type rats, did not have increased fat mass and did not develop insulin resistance or hepatic steatosis. In addition, sEH-P KI rats exhibited enhanced basal cardiac mitochondrial activity associated with an enhanced left ventricular contractility and were protected against cardiac ischemia-reperfusion injury. Conclusion: Our study reveals that sEH-P is a key player in energy and fat metabolism and contributes together with sEH-H to the regulation of cardiometabolic homeostasis. The development of pharmacological inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeutic strategy in the management of obesity and cardiac ischemic complications. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2022. Production and hosting by Elsevier B.V.)
Databáze:	MEDLINE
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