Transferrin fails to provide protection against Fas-induced hepatic injury in mice with deletion of functional transferrin-receptor type 2 |
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Authors: | Vladimir Lesnikov Nicholas Gorden Nelson Fausto Emily Spaulding Jean Campbell Howard Shulman Robert E Fleming H Joachim Deeg |
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Institution: | (1) Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1-100, P.O. Box 19024, Seattle, WA 98109-1024, USA;(2) Departments of Medicine and Pathology, University of Washington, Seattle, WA, USA;(3) Department of Pediatrics and the Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, USA |
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Abstract: | 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 (TfR2Y245X), 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. |
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Keywords: | Hepatocyte apoptosis Fas signaling Apo-transferrin Transferrin receptor 2 Gender effect |
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