title: Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency.
abstract: Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) β/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARβ/δ-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARβ/δ and activation of the HRI-eIF2α-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Zarei
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain.
authors.forename: Rosana
authors.initials: R
authors.lastname: Leiva
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Barniol-Xicota
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain.
authors.forename: Eugènia
authors.initials: E
authors.lastname: Pujol
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Escolano
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Vázquez
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.affiliation: CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pardo
authors.affiliation: CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain.
authors.forename: Águeda
authors.initials: Á
authors.lastname: González-Rodríguez
authors.affiliation: CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
authors.affiliation: Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain Department of Biochemistry and Molecular Biology and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Quesada-López
authors.affiliation: Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain Department of Biochemistry and Molecular Biology and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBEROBN, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.affiliation: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain mvazquezcarrera@ub.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047494:PPAR delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D047494:PPAR delta; D048068:PPAR-beta; C414620:fibroblast growth factor 21; D051701:Activating Transcription Factor 4; D005346:Fibroblast Growth Factors; D019892:eIF-2 Kinase