Transglutaminase type II plays a protective role in hepatic injury.
The up-regulation of "tissue" transglutaminase (TG2) gene has been shown to occur in various pathologies and can lead to severe liver injury; however, its role in the onset of liver damage has not yet been clarified. To address this issue, we have used two experimental settings: carbon tetrachloride (CCl(4))-induced liver injury in wild-type and TG2 knockout mice; and liver biopsies obtained from a large cohort of hepatitis C virus (HCV)-infected patients. Mice lacking TG2 failed to clear the hepatic necrotic tissue formed in response to prolonged CCl(4) exposure (5 weeks) and 60% of them died before the end of the treatment. By contrast, wild-type mice were able to recover after the toxic insult. CCl(4)-treated TG2 null mice showed a derangement of the hepatic lobular architecture and a progressive accumulation of extracellular matrix (ECM) components and inflammatory cells which were not observed in the liver of control animals. Consistent with this protective role, we observed that TG2 levels were much higher (up to 15-fold) during the initial stages of liver fibrosis in HCV-infected individuals (METAVIR = F2) compared with uninfected controls, in which the enzyme protein localized in the hepatocytes facing the periportal infiltrate. By contrast, the enzyme levels decreased in the advanced stages (METAVIR = F3 and F4) and their localization was limited to the ECM. Our data demonstrate that TG2 plays a protective role in the liver injury by favoring tissue stability and repair.
Nardacci
Roberta
R
Istituto Nazionale per le Malattie Infettive, IRCCS L. Spallanzani, Rome.
Lo Iacono
Oreste
O
Ciccosanti
Fabiola
F
Falasca
Laura
L
Addesso
Maria
M
Amendola
Alessandra
A
Antonucci
Giorgio
G
Craxì
Antonio
A
Fimia
Gian Maria
GM
Iadevaia
Valentina
V
Melino
Gerry
G
Ruco
Luigi
L
Tocci
Guido
G
Ippolito
Giuseppe
G
Piacentini
Mauro
M
D000328:Adult; D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control*; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000293:injuries / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009336:Necrosis; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins