title: Hyperthyroidism induces apoptosis in rat liver through activation of death receptor-mediated pathways.
abstract: OBJECTIVE
  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 microg/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-kappaB activation, but persistent exposure (10 days) to triiodothyronine deactivates NF-kappaB 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.
authors.affiliation: Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226 014, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Sinha
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Tiwari
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
authors.forename: Takehiko
authors.initials: T
authors.lastname: Koji
authors.forename: Namratta
authors.initials: N
authors.lastname: Manhas
authors.forename: Leena
authors.initials: L
authors.lastname: Rastogi
authors.forename: Lily
authors.initials: L
authors.lastname: Pal
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shrivastava
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Sahu
authors.forename: Madan M
authors.initials: MM
authors.lastname: Godbole
mesh_terms: D000818:Animals; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8 / Q000378:metabolism; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism; D006980:Hyperthyroidism / Q000139:chemically induced / Q000378:metabolism*; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053218:Receptors, Death Domain / Q000378:metabolism*; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D014284:Triiodothyronine / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D053222:Fas Ligand Protein; D016328:NF-kappa B; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D053218:Receptors, Death Domain; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C514218:pro-nerve growth factor, rat; D014284:Triiodothyronine; C068313:Ngfr protein, rat; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D053181:Caspase 8