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

Diabetes. 2016 Oct;65(10):3185-99. doi: 10.2337/db16-0155. Epub 2016 Aug 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • PPAR delta
  • PPAR-beta
  • fibroblast growth factor 21
  • Activating Transcription Factor 4
  • Fibroblast Growth Factors
  • eIF-2 Kinase