title: Upregulation of rat liver PPARα-FGF21 signaling by a docosahexaenoic acid and thyroid hormone combined protocol.
abstract: Prevention of ischemia-reperfusion liver injury is achieved by a combined omega-3 and thyroid hormone (T3) protocol, which may involve peroxisome-proliferator activated receptor-α (PPAR-α)-fibroblast growth factor 21 (FGF21) signaling supporting energy requirements. Combined docosahexaenoic acid (DHA; daily doses of 300 mg/kg for 3 days) plus 0.05 mg T3/kg given to fed rats elicited higher hepatic DHA contents and serum T3levels, increased PPAR-α mRNA and its DNA binding, with higher mRNA expression of the PPAR-α target genes for carnitine-palmitoyl transferase 1α, acyl-CoA oxidase, and 3-hydroxyl-3-methylglutaryl-CoA synthase 2, effects that were mimicked by 0.1 mg T3/kg given alone or by the PPAR-α agonist WY-14632. Under these conditions, the mRNA expression of retinoic X receptor-α (RXR-α) is also increased, with concomitant elevation of the hepatic mRNA and protein FGF21 levels and those of serum FGF21. It is concluded that PPAR-α-FGF21 induction by DHA combined with T3may involve ligand activation of PPAR-α by DHA and enhanced expression of PPAR-α by T3, with consequent upregulation of the FGF21 that is controlled by PPAR-α. Considering the beneficial effects of PPAR-α-FGF21 signaling on carbohydrate and lipid metabolism, further investigations are required to clarify its potential therapeutic applications in human metabolic disorders. © 2016 BioFactors, 42(6):638-646, 2016.
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Videla
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Virginia
authors.initials: V
authors.lastname: Fernández
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Romina
authors.initials: R
authors.lastname: Vargas
authors.affiliation: School of Medical Technology, Faculty of Health and Odontology, Diego Portales University, Santiago, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Cornejo
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Gladys
authors.initials: G
authors.lastname: Tapia
authors.affiliation: Department of Medical Technology, Faculty of Medicine, University of Chile, Chile.
authors.forename: Nelson
authors.initials: N
authors.lastname: Varela
authors.affiliation: Nutrition Department, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Valenzuela
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Allan
authors.initials: A
authors.lastname: Arenas
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández
authors.affiliation: Nutrition Department, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: María C
authors.initials: MC
authors.lastname: Hernández-Rodas
authors.affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Riquelme
mesh_terms: D000818:Animals; D004281:Docosahexaenoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation
chemical_list: D047493:PPAR alpha; D047490:Retinoid X Receptor alpha; C414620:fibroblast growth factor 21; D014284:Triiodothyronine; D004281:Docosahexaenoic Acids; D005346:Fibroblast Growth Factors
keywords: 3,3′,5-triidothyronine; docosahexaenoic acid; fibroblast growth factor 21; liver signaling; peroxisome-proliferator activated receptor-α