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 language | English (US) |
|---|---|
| Journal | Gastroenterology |
| Volume | 136 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2009 |
Fingerprint
ASJC Scopus subject areas
- Gastroenterology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Role of Transglutaminase 2 in Liver Injury via Cross-linking and Silencing of Transcription Factor Sp1
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.
UR - http://www.scopus.com/inward/record.url?scp=65249179547&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65249179547&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2009.01.007
DO - 10.1053/j.gastro.2009.01.007
M3 - Article
C2 - 19208340
AN - SCOPUS:65249179547
VL - 136
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 5
ER -