Heme-regulated eIF2 alpha kinase modulates hepatic FGF21 and is activated by PPAR beta/delta deficiency

Autor: Zarei, Mohammad, Barroso, Emma, Leiva, Rosana, Barniol-Xicota, Marta, Pujol, Eugènia, Escolano, Carmen, Vazquez, Santiago, Palomer, Xavier, Pardo, Virginia, Gonzalez-Rodriguez, Águeda, Valverde, Ángela M., Quesada-Lopez, Tania, Villarroya, Francesc, WAHLI, Walter, Vazquez-Carrera, Manuel
Přispěvatelé: Faculty of Pharmacy, Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISC), Pediatric Research Institute, Hospital Sant Joan de Déu, Consejo Superior de Investigaciones Científicas, Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBEROBN), Department of Biochemistry and Molecular Biology and IBUB, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Center for Integrative Genomics, Université de Lausanne, Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], This study was partly supported by funds from the Spanish Ministry of the Economy and Competitiveness (SAF2015-65267-R to A.M.V., SAF2014-55725 to F.V., and SAF2012-30708 and SAF2015-64146-R to M.V.-C.) and the European Union European Regional Development Fund. CIBERDEM and CIBEROBN are Instituto de Salud Carlos III Health Institute projects. T.Q.-L. is supported by a CONACyT (National Council for Science and Technology in Mexico) PhD scholarship. W.W. is supported by start-up grants from the Lee Kong Chian School of Medicine, Nanyang Technological University, and by the Region Midi-Pyrenees, France., Instituto de Salud Carlos III [Madrid] (ISC), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Nanyang Technological University (NTU)
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Diabetes
Diabetes, American Diabetes Association, 2016, 65 (10), pp.3185-3199. ⟨10.2337/db16-0155⟩
ISSN: 0012-1797
DOI: 10.2337/db16-0155⟩
Popis: 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)beta/delta deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPAR beta/delta-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 2 alpha (eIF2 alpha) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2 alpha 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 PPAR beta/delta and activation of the HRI-eIF2 alpha-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.
Databáze: OpenAIRE
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