Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency.

M Zarei, E Barroso, R Leiva, M Barniol-Xicota, E Pujol, C Escolano, S Vázquez, X Palomer, V Pardo, Á González-Rodríguez, ÁM Valverde, Tania Paloma Quesada-Lopez, Francesc Villarroya, Walter Wahli, M Vázquez-Carrera

Research output: Contribution to journalJournal articleResearchpeer-review


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) b/d deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARb/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 PPARb/d 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.

Original languageEnglish
Issue number10
Pages (from-to)3185-3199
Publication statusPublished - Oct 2016
Externally publishedYes


  • Activating Transcription Factor 4/genetics
  • Animals
  • Diet, High-Fat/adverse effects
  • Endoplasmic Reticulum Stress/genetics
  • Fibroblast Growth Factors/genetics
  • Immunoblotting
  • Liver/metabolism
  • Male
  • Mice
  • Mice, Knockout
  • PPAR delta/deficiency
  • PPAR-beta/deficiency
  • Phosphorylation/genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • eIF-2 Kinase/genetics


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