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

作　　者：Yoon Seok Roh Ara Cho Zixiong Zhou Hyuneui Jeong Jeong-Eun Park Youn-Soo Cha Suk-Heung Oh Chae-Woong Lim Bumseok Kim 

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

出　　处：《The Journal of Biomedical Research》2017年第1期65-73,共9页生物医学研究杂志（英文版）

基　　金：supported by the National Research Foundation of Korea Grant funded by the Korean Government(No.2008-0061604);supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF),whichis funded by the Ministry of Science,ICT & Future Planning 18(2014R1A1A1006622)

摘　　要：Nonalcoholic steatohepatitis（NASH） is one of the most common liver diseases and a major cause of liver fibrosis worldwide.r-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 al,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 GABA was 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.Nonalcoholic steatohepatitis（NASH） is one of the most common liver diseases and a major cause of liver fibrosis worldwide.r-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 al,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 GABA was 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.

关 键 词：Γ-Aminobutyric acid nonalcoholic steatohepatitis methionine-choline-deficient diet mice GABA 

分 类 号：R575.5[医药卫生—消化系统]