Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease

Mohammad Zarei, Emma Barroso, Xavier Palomer, Jianli Dai, Patricia Rada, Tania Quesada-López, Joan Carles Escolà-Gil, Lidia Cedó, Mohammad Reza Zali, Mahsa Molaei, Reza Dabiri, Santiago Vázquez, Eugènia Pujol, Ángela M Valverde, Francesc Villarroya, Yong Liu, Walter Wahli, Manuel Vázquez-Carrera

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

OBJECTIVE: The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation.

METHODS: Studies were conducted in wild-type and Pparβ/δ-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis.

RESULTS: Increased VLDLR levels were observed in liver of Pparβ/δ-null mice and in Pparβ/δ-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects.

CONCLUSIONS: Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development.

Original languageEnglish
JournalMolecular Metabolism
Volume8
Pages (from-to)117-131
ISSN2212-8778
DOIs
Publication statusPublished - Feb 2018
Externally publishedYes

Keywords

  • Activating Transcription Factor 4/genetics
  • Animals
  • Cell Line, Tumor
  • Female
  • Fibroblast Growth Factors/genetics
  • Humans
  • Liver/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease/metabolism
  • PPAR delta/genetics
  • PPAR-beta/genetics
  • Receptors, LDL/genetics
  • Signal Transduction
  • eIF-2 Kinase/genetics

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