Regulation of transglutaminase-mediated hepatic cell death in alcoholic steatohepatitis and non-alcoholic steatohepatitis.

Abstract

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
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 27 Suppl 2 Pg. 52-7 (Mar 2012) ISSN: 1440-1746 [Electronic] Australia
• PMID: 22320917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Chemical References

• Fatty Acids, Nonesterified
• Karyopherins
• Protein Sorting Signals
• Receptors, Cytoplasmic and Nuclear
• exportin 1 protein
• Ethanol
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins

Topics

• Active Transport, Cell Nucleus
• Alternative Splicing
• Cell Death
• Cell Nucleus (drug effects, enzymology, pathology)
• Ethanol (toxicity)
• Fatty Acids, Nonesterified (toxicity)
• Fatty Liver (enzymology, pathology)
• Fatty Liver, Alcoholic (enzymology, pathology)
• GTP-Binding Proteins
• Hep G2 Cells
• Humans
• Karyopherins (metabolism)
• Liver (drug effects, enzymology, pathology)
• Non-alcoholic Fatty Liver Disease
• Protein Glutamine gamma Glutamyltransferase 2
• Protein Sorting Signals
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Signal Transduction
• Transglutaminases (chemistry, metabolism)