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From the Istituto Nazionale per le Malattie Infettive,* IRCCS "L. Spallanzani", Rome; Dipartimento di Biologia, Università di Roma "Tor Vergata", Rome; Università degli Studi di Palermo, Palermo; Dipartimento di Medicina Sperimentale e Patologia, Università di Roma,"La Sapienza", Rome Biochemistry Laboratory IDI-IRCCS,¶ c/o Dipartimento di Medicina Sperimentale e Biochimica, Università di Roma,"Tor Vergata", Rome, Italy; and the Medical Research Council,|| Toxicology Unit, Leicester University, Leicester, UK
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 (CCl4)-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 CCl4 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. CCl4-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.
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