Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2.
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.
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1-100, P.O. Box 19024, Seattle, WA 98109-1024, USA.
Vladimir
V
Lesnikov
Nicholas
N
Gorden
Nelson
N
Fausto
Emily
E
Spaulding
Jean
J
Campbell
Howard
H
Shulman
Robert E
RE
Fleming
H Joachim
HJ
Deeg
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D053222:Fas Ligand Protein / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007501:Iron / Q000097:blood / Q000633:toxicity; D019189:Iron Metabolism Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008107:Liver Diseases / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011990:Receptors, Transferrin / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014168:Transferrin / Q000378:metabolism* / Q000494:pharmacology; D051020:bcl-X Protein / Q000187:drug effects / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; D053222:Fas Ligand Protein; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D014168:Transferrin; D051020:bcl-X Protein; D007501:Iron; D001219:Aspartate Aminotransferases