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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 ( IF 11.4 ) Pub Date : 2022-03-12 , DOI: 10.1016/j.jare.2022.03.004
Matthieu Leuillier 1 , Thomas Duflot 2 , Séverine Ménoret 3 , Hind Messaoudi 1 , Zoubir Djerada 4 , Déborah Groussard 1 , Raphaël G P Denis 5 , Laurence Chevalier 6 , Ahmed Karoui 7 , Baptiste Panthu 8 , Pierre-Alain Thiébaut 9 , Isabelle Schmitz-Afonso 10 , Séverine Nobis 11 , Cynthia Campart 11 , Tiphaine Henry 11 , Camille Sautreuil 12 , Serge H Luquet 5 , Olivia Beseme 13 , Catherine Féliu 4 , Hélène Peyret 4 , Lionel Nicol 1 , Jean-Paul Henry 1 , Sylvanie Renet 1 , Paul Mulder 1 , Debin Wan 14 , Laurent Tesson 3 , Jean-Marie Heslan 15 , Angéline Duché 16 , Sébastien Jacques 16 , Frédéric Ziegler 17 , Valéry Brunel 17 , Gilles J P Rautureau 18 , Christelle Monteil 7 , Jean-Luc do Rego 11 , Jean-Claude do Rego 11 , Carlos Afonso 10 , Bruce Hammock 14 , Anne-Marie Madec 8 , Florence Pinet 16 , Vincent Richard 19 , Ignacio Anegon 3 , Christophe Guignabert 20 , Christophe Morisseau 14 , Jérémy Bellien 19
Affiliation  

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.



中文翻译:

CRISPR/Cas9 介导的可溶性环氧化物水解酶磷酸酶活性失活可预防肥胖和心脏缺血性损伤

介绍

尽管可溶性环氧化物水解酶 (sEH-H) 的C端水解酶结构域的生理作用已得到充分研究,但其N端磷酸酶活性 (sEH-P)的功能仍然未知。

目标

本研究旨在评估sEH-P在体内的生理作用。

方法

CRISPR/Cas9 用于生成缺乏 sEH-P 活性的新型敲入 (KI) 大鼠系。

结果

sEH-P KI 大鼠将溶血磷脂酸代谢为单酰甘油的能力降低。与野生型大鼠相比,KI 大鼠的生长几乎正常,但体重和脂肪量增加较少,同时胰岛素敏感性增加。这种瘦表型在雄性 KI 大鼠中比在雌性 KI 大鼠中更明显,主要是由于食物消耗减少和能量消耗增加。事实上,sEH-P KI 大鼠的脂肪分解增加,允许提供脂肪酸作为燃料,以在静息条件下和冷暴露下增强棕色脂肪的产热作用。当阻断 PPARγ(一种由细胞内溶血磷脂酸激活的核受体)以及同时抑制 sEH-H 时,生热作用的增强被消除,显示出两个结构域之间的功能相互作用。此外,喂食高脂肪饮食的 sEH-P KI 大鼠没有像野生型大鼠那样体重增加,脂肪量没有增加,也没有出现胰岛素抵抗或肝脂肪变性。此外,sEH-P KI 大鼠表现出与增强的左心室收缩力相关的增强的基础心脏线粒体活性,并受到保护免受心脏缺血再灌注损伤。

结论

我们的研究表明,sEH-P 是能量和脂肪代谢的关键参与者,并与 sEH-H 一起促进心脏代谢稳态的调节。sEH-P 药理学抑制剂的开发对于评估这种有前途的治疗策略在肥胖和心脏缺血并发症管理中的作用似乎至关重要。

更新日期:2022-03-12
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