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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Sp1 Transcription Factor
Liver
Wounds and Injuries
Hepatocytes
Apoptosis
Alcoholic Fatty Liver
Ethanol
transglutaminase 2
Alcohols
Cystamine
Proto-Oncogene Proteins c-met
Alcoholic Liver Diseases
Putrescine
Hepatocyte Growth Factor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Tatsukawa, H., Fukaya, Y., Frampton, G., Martinez-Fuentes, A., Suzuki, K., Kuo, T. F., ... 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

Role of Transglutaminase 2 in Liver Injury via Cross-linking and Silencing of Transcription Factor Sp1. / Tatsukawa, Hideki; Fukaya, Yayoi; Frampton, Gordon; Martinez-Fuentes, Antonio; Suzuki, Kenji; Kuo, Ting Fang; Nagatsuma, Keisuke; Shimokado, Kentaro; Okuno, Masataka; Wu, Jian; Iismaa, Siiri; Matsuura, Tomokazu; Tsukamoto, Hidekazu; Zern, Mark A; Graham, Robert M.; Kojima, Soichi.

In: Gastroenterology, Vol. 136, No. 5, 05.2009.

Research output: Contribution to journalArticle

Tatsukawa, H, Fukaya, Y, Frampton, G, Martinez-Fuentes, A, Suzuki, K, Kuo, TF, Nagatsuma, K, Shimokado, K, Okuno, M, Wu, J, Iismaa, S, Matsuura, T, Tsukamoto, H, Zern, MA, Graham, RM & Kojima, S 2009, 'Role of Transglutaminase 2 in Liver Injury via Cross-linking and Silencing of Transcription Factor Sp1', Gastroenterology, vol. 136, no. 5. https://doi.org/10.1053/j.gastro.2009.01.007
Tatsukawa, Hideki ; Fukaya, Yayoi ; Frampton, Gordon ; Martinez-Fuentes, Antonio ; Suzuki, Kenji ; Kuo, Ting Fang ; Nagatsuma, Keisuke ; Shimokado, Kentaro ; Okuno, Masataka ; Wu, Jian ; Iismaa, Siiri ; Matsuura, Tomokazu ; Tsukamoto, Hidekazu ; Zern, Mark A ; Graham, Robert M. ; Kojima, Soichi. / Role of Transglutaminase 2 in Liver Injury via Cross-linking and Silencing of Transcription Factor Sp1. In: Gastroenterology. 2009 ; Vol. 136, No. 5.
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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.",
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AU - Tatsukawa, Hideki

AU - Fukaya, Yayoi

AU - Frampton, Gordon

AU - Martinez-Fuentes, Antonio

AU - Suzuki, Kenji

AU - Kuo, Ting Fang

AU - Nagatsuma, Keisuke

AU - Shimokado, Kentaro

AU - Okuno, Masataka

AU - Wu, Jian

AU - Iismaa, Siiri

AU - Matsuura, Tomokazu

AU - Tsukamoto, Hidekazu

AU - Zern, Mark A

AU - Graham, Robert M.

AU - Kojima, Soichi

PY - 2009/5

Y1 - 2009/5

N2 - 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.

AB - 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.

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