title: 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 (GABAAR) 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 GABAAR 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 GABAAR subunits decreased in the liver of GalN-treated rats. Remarkably, treating rats with GABA or the GABAAR agonist muscimol, but not the GABABR 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.NEW & NOTEWORTHYAuto- 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.
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.|Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.|Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.|Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Shuanglian
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.|Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.|Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Yun-Yan
authors.initials: YY
authors.lastname: Xiang
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China.|Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Jingxin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Physiology, Shandong University School of Medicine, Jinan, Shandong, People's Republic of China; wlu53@uwo.ca.
authors.forename: Chuanyong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; wlu53@uwo.ca.|Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.|Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.|Department of Physiology, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D005688:Galactosamine; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D005688:Galactosamine; D001418:Baclofen
keywords: GABA currents; GABAARs; GAD; cholangiocyte; hepatocyte