Title: Γ-Aminobutyric acid promotes methionine-choline deficient diet-induced nonalcoholic steatohepatitis

Authors: Yoon Seok Roh1, Ara Cho1,4, Zixiong Zhou1, Hyuneui Jeong1, Jeong-Eun Park2, Youn-Soo Cha2, Suk-Heung Oh3, Chae-Woong Lim1, Bumseok Kim1

Institutions: 1Biosafety Research Institute and Laboratory of Pathology, College of Veterinary Medicine, Chonbuk National University, Iksan-si, Jeollabuk-do 54596, Republic of Korea; 2Department of Food Science and Human Nutrition, Fermented Food Research Center, Chonbuk National University, Jeonju-si, Jeollabuk-do 54896, Republic of Korea; 3Department of Food & Biotechnology, Woosuk University, Jeonju 565701, Republic of Korea; 4Animal Disease & Biosecurity Team, National Institute of Animal Science, Rural Development Administration, Wanjugun 55365, Republic of Korea.

Abstract: Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases and a major cause of liver fibrosis worldwide. Γ-Aminobutyric acid (GABA) is one of the most abundant inhibitory neurotransmitters in the central nervous system. Recently, it has been reported that GABAergic signaling pathways are found in various non-neuronal tissues including the immune system and play a functional role. In the present study, we investigated whether administration of GABA has effects on NASH through its immunomodulatory effects. To test this hypothesis, C57BL/6 mice were fed a methionine–choline-deficient (MCD) diet for 8 weeks. After four weeks into MCD feeding, mice were provided with plain water (control) or water containing 2 mg/mL of GABA for the subsequent 4 weeks. Using this MCD diet-induced NASH model, we found that mice receiving GABA showed more severe steatohepatitis and liver fibrosis than control mice. This increased liver damage was confirmed by higher levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) compared to the control group. In accordance with increased liver steatohepatitis, NASH-related and inflammatory gene expression (collagen α1, tissue inhibitor of metalloproteinase-1, TNF-α) in the liver was markedly increased in GABA-treated mice. Furthermore, GABA directly enhanced production of inflammatory cytokines including IL-6 and TNF-α in LPS activated RAW macrophage cells and increased TIB–73 hepatocyte death. Such effects were abolished when GABAwas treated with bicuculline, a competitive antagonist of GABA receptors. These results suggest that oral administration of GABA may be involved in changes of the liver immune milieu and conferred detrimental effects on NASH progression.

Keywords: Γ-Aminobutyric acid, nonalcoholic steatohepatitis, methionine–choline-deficient diet, mice, GABA

Full Text:  jbr-2016-k0007.pdf

J Biomed Res published on July 29th, 2016, doi:10.7555/JBR.31.2016K0007