Role of transglutaminase 2 in liver injury via cross-linking and silencing of transcription factor Sp1

Gastroenterology. 2009 May;136(5):1783-95.e10. doi: 10.1053/j.gastro.2009.01.007. Epub 2009 Jan 14.

Abstract

Background & aims: Despite high morbidity and mortality of alcoholic liver disease worldwide, the molecular mechanisms underlying alcohol-induced liver cell death are not fully understood. Transglutaminase 2 (TG2) is a cross-linking enzyme implicated in apoptosis. TG2 levels and activity are increased in association with various types of liver injury. However, how TG2 induces hepatic apoptosis is not known.

Methods: Human hepatic cells or primary hepatocytes from rats or TG2+/+ and TG2-/- mice were treated with ethanol. Mice were administered anti-Fas antibody or alcohol. Liver sections were prepared from patients with alcoholic steatohepatitis. Changes in TG2 levels, Sp1 cross-linking and its activities, expression of hepatocyte growth factor receptor, c-Met, and hepatic apoptosis were measured.

Results: Ethanol induced apoptosis in hepatic cells, enhanced activity and nuclear accumulation of TG2 as well as accumulation of cross-linked and inactivated Sp1, and reduced expression of the Sp1-responsive gene, c-Met. These effects were rescued by TG2 knockdown, restoration of functional Sp1, or addition of hepatocyte growth factor, whereas apoptosis was reproduced by Sp1 knockdown or TG2 overexpression. Compared with TG2+/+ mice, TG2-/- mice showed markedly reduced hepatocyte apoptosis and Sp1 cross-linking following ethanol or anti-Fas treatment. Treatment of TG2+/+ mice with the TG2 inhibitors putrescine or cystamine blocked anti-Fas-induced hepatic apoptosis and Sp1 silencing. Moreover, enhanced expression of cross-linked Sp1 and TG2 was evident in hepatocyte nuclei of patients with alcoholic steatohepatitis.

Conclusions: TG2 induces hepatocyte apoptosis via Sp1 cross-linking and inactivation, with resultant inhibition of the expression of c-Met required for hepatic cell viability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cells, Cultured
  • Ethanol / pharmacology*
  • Fatty Liver, Alcoholic / metabolism*
  • Fatty Liver, Alcoholic / pathology
  • GTP-Binding Proteins / metabolism*
  • Gene Silencing*
  • Guinea Pigs
  • Hepatocytes / metabolism
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*
  • Transcriptional Activation
  • Transfection
  • Transglutaminases / metabolism*

Substances

  • Sp1 Transcription Factor
  • Ethanol
  • transglutaminase 2
  • Transglutaminases
  • Proto-Oncogene Proteins c-met
  • GTP-Binding Proteins

Associated data

  • GEO/GSE10285