Heme-regulated eIF2a kinase modulates hepatic FGF21 and is activated by PPARß/d deficiency
Por:
Zarei M, Barroso E, Leiva R, Barniol-Xicota M, Pujol E, Escolano C, Vázquez S, Palomer X, Pardo V, González-Rodríguez Á, Valverde ÁM, Quesada-López T, Villarroya-Gombau F, Wahli W and Vázquez-Carrera M
Publicada:
1 oct 2016
Ahead of Print:
2 ago 2016
Resumen:
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) ß/d deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARß/d-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 2a (eIF2a) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2a 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 PPARß/d and activation of the HRI-eIF2a-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.
Filiaciones:
Zarei M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Pediatric Research Institute-Hospital Sant Joan de Déu
Barroso E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Pediatric Research Institute-Hospital Sant Joan de Déu
Leiva R:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Barniol-Xicota M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Pujol E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Escolano C:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Vázquez S:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Palomer X:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Pediatric Research Institute-Hospital Sant Joan de Déu
Pardo V:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
González-Rodríguez Á:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
Valverde ÁM:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
Quesada-López T:
Pediatric Research Institute-Hospital Sant Joan de Déu Department of Biochemistry and Molecular Biology and IBUB, University of Barcelona, Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBEROBN)-Instituto de Salud Carlos III
Villarroya-Gombau F:
Pediatric Research Institute-Hospital Sant Joan de Déu Department of Biochemistry and Molecular Biology and IBUB, University of Barcelona, Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBEROBN)-Instituto de Salud Carlos III
Wahli W:
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France
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