肝细胞GABA能信号系统的新角色：急性酒精性肝损伤中的肝保护作用

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. The GABAergic siganaling system in the brain plays an important role in the pathogenesis of alcoholism and alcohol dependence. We recently found that an A type GABA receptor (GABAAR) mediated auto- or para-crine GABAergic signaling system is functionly expressed in both human and rat hepatocytes. Notably, activation of this system protects the liver against experimental liver injury. Keeping this in mind, we want to know 1).whether ethanol affect hepatic GABAergic signaling system, and 2) whether hepatic GABAergic sigaling system plays a role in ethanol's hepatotoxicity and the underlying mechanisms. Our preliminary study shows that hepatic GABAergic signaling system is inhibited in ethanol-induced acute hepatic liver injury in mice, and the expression of glucose regulated protein 78 (GRP78), which is one of the markers of endoplasmic reticulum stress response (ERSR), is increased in the liver. Pretreatment with GABA reverses ethanol-induced increase of GRP78 and protects the liver against ethanol's hepatotoxicity. We thus hypothesize that interference with hepatic GABAergic sigaling system by ethanol may lead to ethanol-induced liver injury. Activation of hepatic GABAergic system may protect the liver against ethanol's hepatotoxicity by inhibition of excess ERSR in ethanol-induced liver injury. In this study, we will investigate the role of hepatic GABAergic signaling system and ER related mechanisms in ethanol-induced acute liver injury in mice and in HepG2 cell line. Our study may lead to a better understanding of the pathogenesis of alcoholic liver disease and new targets for therapies to support recovery from ethanol associated liver diseases.

γ-氨基丁酸（gamma-aminobutyric acid，GABA）是一种主要的抑制性神经递质。酒精对中枢GABA能（GABAergic）系统的影响与酒精中毒和酒精依赖密切相关。我们最近发现肝细胞也表达A型GABA受体介导的GABA能信号系统，激活该系统可保护肝功能。肝细胞GABA能系统在酒精性肝损伤中的作用尚不明确。我们预实验发现，酒精性肝损伤小鼠肝细胞GABA能系统被抑制，而内质网应激反应（ERSR）的标志物GRP78的表达显著上调；GABA预处理可下调GRP78表达并抑制酒精性肝损伤。由此我们假设：酒精对肝细胞GABA能系统的干扰作用可能是酒精性肝损伤的重要机制；激活肝脏GABA能系统可通过抑制过度的ERSR拮抗酒精的肝毒性作用。本课题将利用酒精性肝损伤小鼠和HepG2细胞模型，基于ERSR探讨肝细胞GABA能系统在急性酒精肝损伤中的作用和机制，为临床防治酒精性肝病提供新的策略。

本项目探讨了肝脏gamma-aminobutyric acid （GABA）系统在急性酒精性肝损伤中的作用。结果发现，与生理盐水处理的小鼠相比，谷氨酸脱羧酶（glutamic acid decarboxylase，GAD）和A型GABA受体（GABAAR）亚单位的蛋白表达水平在酒精处理的小鼠肝脏中明显升高。与小鼠实验的结果相似，我们利用临床上因外伤行肝部分切除术的肝脏标本行免疫荧光染色发现，在具有5年以上的酗酒史的病人肝脏中，GAD的表达水平也显著高于不酗酒或者低于5年的酗酒史的病人。用GABA或者选择性GABAAR激动剂muscimol预处理小鼠后，酒精导致的肝损伤可被明显改善，但是GABAAR阻断剂却不能逆转酒精的肝毒性作用。肝细胞GABA-GABAAR系统的肝保护作用可能与其下调酒精选择性诱导激活的内质网应激反应中IRE1alpha-ASK1-JNK信号通路有关。本课题的研究将对临床上认识酒精导致的肝功能损伤提供新的思路，为临床上治疗和防治酒精性肝病提供新的理论依据。