Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2.

Publication Type:

Journal Article


Apoptosis : an international journal on programmed cell death, Volume 13, Issue 8, p.1005-12 (2008)


2008, Animals, APOPTOSIS, Apoptosis Regulatory Proteins, Aspartate Aminotransferases, bcl-X Protein, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Cytokine Analysis Core Facility, Cytoprotection, Drug-Induced Liver Injury, Experimental Histopathology Core Facility, Fas Ligand Protein, Female, Genomics Core Facility, Hepatocytes, Iron, Iron Metabolism Disorders, Liver Diseases, Male, MICE, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Receptors, Transferrin, Sex Characteristics, Shared Resources, Signal Transduction, Transferrin


We reported previously that Fas-induced hepatic failure in normal mice was attenuated or prevented by exogenous transferrin (Tf), particularly apoTf. Here we show in C57BL6J/129 mice with genetic inactivation of transferrin receptor 2 (TfR2(Y245X)), that Fas-induced hepatotoxicity (apoptosis; rise in plasma aspartate aminotransferase (AST) levels) was comparable to that in wild-type mice, but was not modified by pretreatment with Tf. Rises in plasma AST were preceded by a decline in serum iron levels. AST elevations and iron declines were more profound in female than in male mice. Female mice also showed higher baseline levels of Bcl-xL in hepatocytes, which declined significantly upon treatment with agonistic anti-Fas antibody. These data confirm the cytoprotective function of Tf, and show a novel property of TfR2. Both apoptotic Fas responses and cytoprotective effects of Tf were associated with significant shifts in plasma iron levels, which quantitatively differed between male and female mice.