Hyperthyroidism induces apoptosis in rat liver through activation of death receptor-mediated pathways

Background/Aims: The molecular basis of hepatic dysfunction in thyrotoxicosis is not fully understood. Here, we investigated the effect of altered thyroidal status on death receptor pathways including p75 neurotrophin receptor (p75NTR), a member of tumor necrosis factor (TNF) receptor superfamily, in rat liver. Methods: Hyperthyroidism was induced in Sprague-Dawley rats by daily injections of triiodothyronine in a dose of 12.5 mu g/100 g body weight for 10 days. Results: Terminal deoxynucleotide-transferase-mediated dUTP nick end labeling assay and caspase-3 activation data confirmed apoptosis in hyperthyroid rat liver. We observed the elevated levels of death ligands, TNF-alpha, Fas ligand and their cognate receptors, TNF-receptor-1 and Fas, and 8-fold increase in caspase-8 activation in hyperthyroid rat liver (p < 0.001). We demonstrated for the first time that hyperthyroidism elevates p75NTR levels and its ligands, pro-nerve growth factor and pro-brain-derived neurotrophic factor, in rat liver. Further we showed that most of the apoptotic cells in hyperthyroid liver express p75NTR. We also demonstrated that triiodothyronine administration to rats causes NF-KB activation, but persistent exposure (10 days) to triiodothyronine deactivates NF-KB leading to sustained c-Jun N-terminal kinase (JNK) activation. Conclusions: This study showed that hyperthyroidism-induced apoptosis in rat liver involves the activation of death receptor-mediated pathways, including p75NTR. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.