Protective roles of hepatic GABA signaling in acute liver injury of rats

Abstract

γ-Aminobutyric acid (GABA) is produced by various cells through the catalytic activity of glutamic acid decarboxylase (GAD). Activation of type-A GABA receptor (GABAR) inhibits stem cell proliferation but protects differentiated cells from injures. The present study investigated hepatic GABA signaling system and the role of this system in liver physiology and pathophysiology. RT-PCR and immunoblot assays identified GAD and GABAR subunits in rat livers and in HepG2 and Clone 9 hepatocytes. Patch-clamp recording detected GABA-induced currents in Clone 9 hepatocytes and depolarization in WITT cholangiocytes. The function of hepatic GABA signaling system in rats was examined using models of d-galactosamine (GalN)-induced acute hepatocytic injury in vivo and in vitro. The expression of GAD increased whereas GABAR subunits decreased in the liver of GalN-treated rats. Remarkably, treating rats with GABA or the GABAR agonist muscimol, but not the GABAR agonist baclofen, protected hepatocytes against GalN toxicity and improved liver function. In addition, muscimol treatment decreased the formation of pseudobile ductules and the enlargement of hepatocytic canaliculi in GalN-treated rats. Our results revealed that a complex GABA signaling system exists in the rat liver. Activation of this intrahepatic GABAergic system protected the liver against toxic injury. Auto- and paracrine GABAergic signaling systems exist in the rat hepatocytes and cholangiocytes. Activation of GABA signaling protects liver function from d-galactosamine injury by reducing toxic impairment of hepatocytes and by decreasing cholangiocyte proliferation.

Effects of gamma-aminobutyric acid and piperine on gene regulation in pig kidney epithelial cell lines

“…Neurotransmitter GABA has been widely studied in human patients as treatment for neuronal diseases including Alzheimer's disease [18]. In addition, several studies have shown that GABA plays an important role in non-neuronal tissues and that it can be used to treat diseases including liver injury [19]. In kidney, GABA is shown to have anti-inflammatory properties and promote fibroblast proliferation [20].…”

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

“…As shown in Table , from the first to the third day, mice in the GABA + ethanol, muscimol + ethanol and bicuculline + ethanol groups were i.p. injected daily with GABA (1.5 mg kg −1 body weight daily; Sigma‐Aldrich, St. Louis, MO, USA) (Xiang et al, ), muscimol (GABA A R agonist, 1.2 mg kg −1 body weight daily; Sigma‐Aldrich) (Wang et al, ; Xiang et al, ) and bicuculline (GABA A R antagonist, 2.0 mg kg −1 body weight daily; Sigma‐Aldrich) (Soltani et al, ; Wang et al, ), respectively. Mice in the control and ethanol groups were i.p.…”

“…Early studies have revealed that both rat and human hepatocytes contain high concentrations of GABA (Minuk, ) and express GABA A R subunits (Minuk et al, ).Recently, we demonstrated that GABA A R‐mediated auto‐ and paracrine signaling mechanisms exist in different types of cells in the liver. Moreover, the hepatic toxin d ‐galactosamine alters the expression of GABA A R in hepatocytes and activation of hepatic GABA signaling protects rat liver function from d ‐galactosamine injury (Wang et al, ). Other studies have shown that acute ingestion of ethanol raises plasma GABA levels in humans (Bannister, Levy, Bolton, & Losowsky, ) and that GABA protects hepatocytes from ethanol cytotoxicity in vitro through unknown mechanism(s) (Norikura, Kojima‐Yuasa, Suzuura, & Matsui‐Yuasa, ).…”

A novel sympathetic neuronal GABAergic signalling system regulates NE release to prevent ventricular arrhythmias after acute myocardial infarction

“…15 Nonetheless, the mechanisms require further investigation. 18 Outside the CNS, many studies have discovered new functions of this system in peripheral organs such as the pancreatic islet, 19 liver 20,21 and human fallopian tube, 22 as well as in the cardiovascular system. 16 Moreover, GABA A and GABA B receptors participate in cardiac function modulation by tonic sympathetic outflow in the paraventricular nucleus of the hypothalamus 17 ; exogenous GABA in the CNS also mediates autonomic nerve activity to decrease coronary vessel resistance and exert an anti-arrhythmic effect on ischemic heart tissue.…”

“…16 Moreover, GABA A and GABA B receptors participate in cardiac function modulation by tonic sympathetic outflow in the paraventricular nucleus of the hypothalamus 17 ; exogenous GABA in the CNS also mediates autonomic nerve activity to decrease coronary vessel resistance and exert an anti-arrhythmic effect on ischemic heart tissue. 18 Outside the CNS, many studies have discovered new functions of this system in peripheral organs such as the pancreatic islet, 19 liver 20,21 and human fallopian tube, 22 as well as in the cardiovascular system. Injection of exogenous GABA via the caudal vein significantly decreases the incidence of arrhythmias induced by aconitine, 23 indicating a potential peripheral therapeutic effect of the GABAergic signalling system in the treatment of cardiovascular diseases such as heart failure, MI and arrhythmias.…”