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

Mohammad Zarei1, Emma Barroso1, Rosana Leiva2

  • 1Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain.

Diabetes
|August 4, 2016
PubMed

Insights

Peroxisome proliferator-activated receptor (PPAR) β/δ deficiency increases hepatic fibroblast growth factor 21 (FGF21) via the heme-regulated eukaryotic translation initiation factor 2α (HRI) pathway. HRI activation may target hepatic FGF21 for metabolic disorders.

Area of Science:

  • Metabolic Regulation
  • Hormonal Signaling

Background:

  • Fibroblast growth factor 21 (FGF21) regulates carbohydrate and lipid metabolism, making it a therapeutic target for diabetes.
  • The role of peroxisome proliferator-activated receptor (PPAR) β/δ in hepatic FGF21 regulation remains unclear.

Purpose of the Study:

  • To investigate the role of PPAR β/δ deficiency in hepatic FGF21 regulation.
  • To elucidate the molecular mechanisms linking PPAR β/δ, heme-regulated eukaryotic translation initiation factor 2α (HRI), and FGF21 expression.

Main Methods:

  • Utilized PPAR β/δ-null mice and primary hepatocytes with siRNA knockdown of PPAR β/δ.
  • Assessed Fgf21 expression, protein levels of HRI, phosphorylated eIF2α, and activating transcription factor 4 (ATF4).
  • Investigated the effect of FGF21 neutralization on endoplasmic reticulum stress and the impact of HRI pharmacological activation.

Main Results:

  • PPAR β/δ deficiency and knockdown led to increased hepatic Fgf21 expression.
  • Increased Fgf21 was associated with enhanced HRI, phosphorylated eIF2α, and ATF4 levels.
  • HRI activation attenuated tunicamycin-induced endoplasmic reticulum stress, reduced lipid-induced hepatic steatosis, and improved glucose intolerance, effects dependent on FGF21.

Conclusions:

  • PPAR β/δ deficiency activates the HRI-eIF2α-ATF4 pathway, leading to increased hepatic FGF21.
  • HRI is a key regulator of hepatic FGF21 and plays a role in mitigating metabolic stress.
  • HRI represents a potential therapeutic target for modulating hepatic FGF21 levels in metabolic diseases.

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