Role of Transglutaminase 2 in Liver Injury via Cross-linking and Silencing of Transcription Factor Sp1

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.

Tissue transglutaminase contributes to the all-trans-retinoic acid–induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia

“…Nuclear TG2 is able to directly cross-link and inactivate the Sp1 transcription factor participating in the development of alcoholic liver disease. 26 It was also demonstrated that TG2 modulates the transcriptional activity of the retinoblastoma protein by its cross-linking or kinase activity. [27][28][29] In the cytoplasm, TG2 can catalyze polymer formation of I-B␣ monomers, thereby it contributes to the activation of nuclear factor-B in microglia and breast cancer cells.…”

Transglutaminases and Disease: Lessons From Genetically Engineered Mouse Models and Inherited Disorders

“…Consistent with a protective role for TG2 in liver damage, treatment of C57BL/6 TG2-deficient mice with the hepatotoxin carbon tetrachloride resulted in an increased incidence of death postinjury, relative to control C57BL/6 mice, an effect associated with an increased inflammatory response and increased ECM accumulation (204). In contrast, consistent with a proapoptotic role for TG2 is the finding that compared with their wild-type mixed-strain (SVJ129-C57BL/6) littermates, apoptosis of hepatocytes from TG2 Ϫ/Ϫ mice was markedly reduced following treatment of isolated hepatocytes with ethanol or treatment of animals with a low dose (0.1 g/g body wt) of the anti-Fas antibody Jo2, which is a known, potent inducer of endothelial cell and hepatocyte apoptosis that contributes to alcohol-induced liver damage (281). This finding contrasts with that of an earlier study reporting increased death of mixed-strain (SVJ129-C57BL/6) TG2-deficient mice relative to wild-type FVB mice, when treated with a high dose (1 g/g body wt) of Jo2 (240).…”

Lamin aggregation is an early sensor of porphyria-induced liver injury

“…In this case, formation of such aggregates may be due to the activation of TG2 given that ethanol administration to mice results in TG2 activation and translocation to the nucleus coupled with crosslinking of Sp1 (Tatsukawa et al, 2009). Also, porphyria is not a feature of alcohol-related liver injury so a direct PPIX-mediated crosslinking or aggregation could not be invoked.…”