Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease,Cellular and Molecular Gastroenterology and Hepatology

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Soluble Epoxide Hydrolase Hepatic Deficiency Ameliorates Alcohol-Associated Liver Disease
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-10-15 , DOI: 10.1016/j.jcmgh.2020.10.002
Aline Mello ₁ , Ming-Fo Hsu ₁ , Shinichiro Koike ₁ , Bryan Chu ₁ , Jeff Cheng ₂ , Jun Yang ₂ , Christophe Morisseau ₃ , Natalie J Torok ₄ , Bruce D Hammock ₃ , Fawaz G Haj ₅

Affiliation

Background & Aims

Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD is mostly unexplored.

Methods

To decipher the role of hepatic sEH in ALD, we generated mice with liver-specific sEH disruption (Alb-Cre; Ephx2^fl/fl). Alb-Cre; Ephx2^fl/fl and control (Ephx2^fl/fl) mice were subjected to an ethanol challenge using the chronic plus binge model of ALD and hepatic injury, inflammation, and steatosis were evaluated under pair-fed and ethanol-fed states. In addition, we investigated the capacity of pharmacologic inhibition of sEH in the chronic plus binge mouse model.

Results

We observed an increase of hepatic sEH in mice upon ethanol consumption, suggesting that dysregulated hepatic sEH expression might be involved in ALD. Alb-Cre; Ephx2^fl/fl mice presented efficient deletion of hepatic sEH with corresponding attenuation in sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. In addition, targeted metabolomics identified lipid mediators that were impacted significantly by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacologic inhibition of sEH recapitulated the effects of hepatic sEH deficiency and abrogated injury, inflammation, and steatosis caused by ethanol feeding.

Conclusions

These findings elucidated a role for sEH in ALD and validated a pharmacologic inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach.

中文翻译：

可溶性环氧化物水解酶肝缺陷可改善酒精相关肝病

背景与目标

酒精相关性肝病 (ALD) 是全球肝脏相关发病率和死亡率的重要原因，而且治疗方法有限。可溶性环氧化物水解酶 (sEH; Ephx2 ) 是一种主要的细胞溶质酶，在肝脏中高度表达并与肝功能有关，但其在 ALD 中的作用大多未被探索。

方法

为了破译肝脏 sEH 在 ALD 中的作用，我们产生了肝脏特异性 sEH 破坏的小鼠（Alb -Cre；Ephx2 ^fl/fl）。Alb- Cre; Ephx2 ^fl/fl和对照 ( Ephx2 ^fl/fl ) 小鼠使用 ALD 的慢性加狂暴模型进行乙醇攻击，并在成对喂养和乙醇喂养状态下评估肝损伤、炎症和脂肪变性。此外，我们研究了慢性加暴食小鼠模型中 sEH 的药理抑制能力。

结果

我们观察到乙醇消耗后小鼠肝脏 sEH 增加，表明肝脏 sEH 表达失调可能与 ALD 相关。Alb- Cre; Ephx2 ^fl/fl小鼠表现出肝脏 sEH 的有效缺失，sEH 活性相应减弱，脂质环氧化物/二醇比率发生变化。一致地，肝脏 sEH 缺乏改善了乙醇引起的肝损伤、炎症和脂肪变性。此外，靶向代谢组学确定了受肝脏 sEH 缺乏显着影响的脂质介质。此外，肝脏 sEH 缺乏与乙醇诱导的肝内质网和氧化应激的显着减弱有关。值得注意的是，sEH 的药理学抑制概括了肝脏 sEH 缺乏和消除乙醇喂养引起的损伤、炎症和脂肪变性的影响。