Protective roles of hepatic gamma-aminobutyric acid signaling in acute ethanol exposure-induced liver injury.

Abstract

Alcoholic liver disease (ALD) is a consequence of heavy and prolonged alcohol consumptions. We previously demonstrated a hepatic gamma-aminobutyric acid (GABA) signaling system that protects the liver from toxic injury. The present study was designed to investigate the role of the hepatic GABA signaling system in the process of acute ethanol exposure-induced liver injury. Our results showed that the expression of GABA synthesizing enzyme glutamic acid decarboxylase and type A GABA receptor (GABAA R) subunits was upregulated in ethanol-treated mice compared with saline-treated controls. Remarkably, pretreatment of mice with GABA (1.5mg kg-1 body weight, intraperitoneal injection [i.p.]) or with the GABAA R agonist muscimol (1.2mg kg-1 body weight, i.p.) protected the liver against ethanol toxicity and improved liver function, whereas pretreatment of mice with the GABAA R antagonist bicuculline (2.0mg kg-1 body weight, i.p.) worsened the liver function. Further analyses suggest that GABAA R-mediated signaling protects the liver from ethanol injury by, at least partially, inhibiting the IRE1α-ASK1-JNK pro-apoptotic pathway in hepatocytes in the process of ethanol-induced endoplasmic reticulum stress response.