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CRISPR/Cas9-mediated Inactivation of the Phosphatase Activity of Soluble Epoxide Hydrolase Prevents Obesity and Cardiac Ischemic Injury
Journal of Advanced Research  (IF12.822),  Pub Date : 2022-03-12, DOI: 10.1016/j.jare.2022.03.004
Matthieu Leuillier, Thomas Duflot, Séverine Ménoret, Hind Messaoudi, Zoubir Djerada, Déborah Groussard, Raphaël G.P. Denis, Laurence Chevalier, Ahmed Karoui, Baptiste Panthu, Pierre-Alain Thiébaut, Isabelle Schmitz-Afonso, Séverine Nobis, Cynthia Campart, Tiphaine Henry, Camille Sautreuil, Serge H. Luquet, Olivia Beseme, Jérémy Bellien

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. 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.