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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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

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

doi

10.1053/j.gastro.2009.01.007

subject

Has Abstract

pub_date

2009-05-01 00:00:00

pages

1783-95.e10

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(09)00013-4

journal_volume

136

pub_type

杂志文章

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