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

Hideki Tatsukawa, Yayoi Fukaya, Gordon Frampton, Antonio Martinez-Fuentes, Kenji Suzuki, Ting Fang Kuo, Keisuke Nagatsuma, Kentaro Shimokado, Masataka Okuno, Jian Wu, Siiri Iismaa, Tomokazu Matsuura, Hidekazu Tsukamoto, Mark A Zern, Robert M. Graham, Soichi Kojima

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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.

Original languageEnglish (US)
JournalGastroenterology
Volume136
Issue number5
DOIs
StatePublished - May 2009

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ASJC Scopus subject areas

  • Gastroenterology

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Tatsukawa, H., Fukaya, Y., Frampton, G., Martinez-Fuentes, A., Suzuki, K., Kuo, T. F., Nagatsuma, K., Shimokado, K., Okuno, M., Wu, J., Iismaa, S., Matsuura, T., Tsukamoto, H., Zern, M. A., Graham, R. M., & Kojima, S. (2009). Role of Transglutaminase 2 in Liver Injury via Cross-linking and Silencing of Transcription Factor Sp1. Gastroenterology, 136(5). https://doi.org/10.1053/j.gastro.2009.01.007