Document Detail


Regulation of transglutaminase-mediated hepatic cell death in alcoholic steatohepatitis and non-alcoholic steatohepatitis.
MedLine Citation:
PMID:  22320917     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Background and Aim:  Transglutaminase 2 (TG2), catalyzing crosslinking between lysine and glutamine residues, is involved in many liver diseases. We previously reported that TG2, induced in the nucleus of ethanol- or free fatty acids (FFAs)-treated hepatic cells, crosslinks and inactivates a transcription factor Sp1, leading to reduced expression of c-Met and thereby caspase independent hepatic apoptosis in culture systems, animal models, and both alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) patients. FFAs increase endoplasmic reticulum (ER) stress, NFkB activation and nuclear TG2 (nTG2) through pancreatic ER kinase (PERK)-dependent pathway, whereas ethanol induces nTG2 via retinoid signaling. However, the molecular mechanism by which ethanol/FFAs induce nuclear localization of TG2 has been unclear. Method:  A similar nTG2-mediated cell death is induced in acyclic retinoid (ACR)-treated hepatocellular carcinoma. Using cultured cells, we investigated how to control this novel apoptotic pathway by regulating nuclear localization of TG2. Results:  TG2 is composed of N-terminal b-sandwich, catalytic core, b-barrel 1, and C-terminal b-barrel 2 domains. In a previous work, we identified a 14 amino acid nuclear localization signal (NLS) within the b-barrel 1 domain and a putative leucine-rich nuclear export signal (NES) at position 657 to 664 (LHMGLHKL) near the C-terminus in the b-barrel 2 domain, and found that ACR downregulated exportin-1 levels, thereby accumulation of TG2 in the nucleus. Here, we found that both ethanol and FFAs provoked generation of truncated short form of TG2 (TG2-S) defects in the putative NES at least in part through alternative splicing, thereby causing accumulation of TG2-S in the nucleus. Conclusion:  The generation of TG2-S in ethanol or FFAs-treated hepatic cells is a novel therapeutic target for prevention of hepatic cell death associated with ASH/NASH.
Authors:
Soichi Kojima; Ting-Fang Kuo; Hideki Tatsukawa
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of gastroenterology and hepatology     Volume:  27 Suppl 2     ISSN:  1440-1746     ISO Abbreviation:  J. Gastroenterol. Hepatol.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-02-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8607909     Medline TA:  J Gastroenterol Hepatol     Country:  Australia    
Other Details:
Languages:  eng     Pagination:  52-7     Citation Subset:  IM    
Copyright Information:
© 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
Affiliation:
Molecular Ligand Biology Research Team, Chemical Genomics Research Group, Chemical Biology Department, RIKEN Advanced Science Institute, Saitama, Japan Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Tokyo, Japan.
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