Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency.
Détails
ID Serval
serval:BIB_ED770D75B558
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency.
Périodique
Diabetes
ISSN
1939-327X (Electronic)
ISSN-L
0012-1797
Statut éditorial
Publié
Date de publication
10/2016
Peer-reviewed
Oui
Volume
65
Numéro
10
Pages
3185-3199
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
Activating Transcription Factor 4/genetics, Activating Transcription Factor 4/metabolism, Animals, Diet, High-Fat/adverse effects, Endoplasmic Reticulum Stress/genetics, Endoplasmic Reticulum Stress/physiology, Fibroblast Growth Factors/genetics, Fibroblast Growth Factors/metabolism, Immunoblotting, Liver/metabolism, Male, Mice, Mice, Knockout, PPAR delta/deficiency, PPAR delta/genetics, PPAR delta/metabolism, PPAR-beta/deficiency, PPAR-beta/genetics, PPAR-beta/metabolism, Phosphorylation/genetics, Phosphorylation/physiology, Reverse Transcriptase Polymerase Chain Reaction, eIF-2 Kinase/genetics, eIF-2 Kinase/metabolism
Pubmed
Open Access
Oui
Création de la notice
15/12/2016 10:21
Dernière modification de la notice
20/08/2019 17:15