CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury - Université Claude Bernard Lyon 1 Accéder directement au contenu
Article Dans Une Revue International journal of advanced research Année : 2023

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

Serge Luquet
Angéline Duché
  • Fonction : Auteur
Frédéric Ziegler
  • Fonction : Auteur
Valéry Brunel
  • Fonction : Auteur
Florence Pinet
  • Fonction : Auteur

Résumé

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 PPARc, 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 pharmacolog-ical inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeu-tic strategy in the management of obesity and cardiac ischemic complications.
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Dates et versions

hal-03836917 , version 1 (02-11-2022)

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Matthieu Leuillier, Thomas Duflot, Séverine Ménoret, Hind Messaoudi, Zoubir Djerada, et al.. CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury. International journal of advanced research, 2023, 43, pp.163-174. ⟨10.1016/j.jare.2022.03.004⟩. ⟨hal-03836917⟩
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