Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury.
Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury.
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DOI：
10.1038/srep24277
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发表时间：
2016-04-14
影响因子：
4.6
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Xu J;Xu Y;Li Y;Jadhav K;You M;Yin L;Zhang Y
肝脏是控制肝脏和全身稳态的主要器官。肝脏代谢失调可导致肝损伤。以往的研究表明，羧酸酯酶1（CES1）调节肝脏甘油三酯代谢，防止肝脏脂肪变性。在本研究中，我们调查了CES1是否在酒精性肝病（ALD）和蛋氨酸和胆碱缺乏（MCD）饮食诱导的肝损伤的发展中发挥作用。酒精性脂肪性肝炎患者肝细胞核因子4α（HNF 4 α）和CES1均显著降低。酒精抑制原代肝细胞中HNF 4 α和CES 1的表达。HNF4α通过与CES1近端启动子直接结合来调控CES1的表达。CES1的整体失活加重了酒精或MCD饮食诱导的肝脏炎症和肝损伤，可能是由于乙醛和活性氧产生增加以及线粒体功能障碍。肝CES1的敲低加重了乙醇诱导的脂肪性肝炎。这些数据表明，CES1在防止酒精或MCD饮食诱导的肝损伤方面起着至关重要的作用。
The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.