title: T₃-induced liver AMP-activated protein kinase signaling: redox dependency and upregulation of downstream targets.
abstract: OBJECTIVE
  To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver.
  
  
  METHODS
  Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T3/kg or T3 vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T3. Measurements included plasma and liver 8-isoprostane and serum β-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA).
  
  
  RESULTS
  T3 upregulates AMPK signaling, including the upstream kinases Ca(2+)-calmodulin-dependent protein kinase kinase-β and transforming growth factor-β-activated kinase-1, with T3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1α (CPT-1α) activation and higher expression of peroxisome proliferator-activated receptor-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes CPT-1α, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T3 induced a significant increase in the serum levels of β-hydroxybutyrate, a surrogate marker for hepatic FAO.
  
  
  CONCLUSIONS
  T3 administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T3 preconditioning against ischemia-reperfusion injury.
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Videla
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Virginia
authors.initials: V
authors.lastname: Fernández
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Cornejo
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Romina
authors.initials: R
authors.lastname: Vargas
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Paula
authors.initials: P
authors.lastname: Morales
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Juan
authors.initials: J
authors.lastname: Ceballo
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Escudero
authors.affiliation: Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile.
authors.forename: Oscar
authors.initials: O
authors.lastname: Escobar
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000097:blood; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010084:Oxidation-Reduction; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014284:Triiodothyronine / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D005227:Fatty Acids; D012333:RNA, Messenger; D014284:Triiodothyronine; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D055372:AMP-Activated Protein Kinases; D020155:3-Hydroxybutyric Acid
keywords: AMP-activated protein kinase; Fatty acid oxidation; Liver; N-acetylcysteine; Thyroid hormone