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Title: Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease
Authors: Mohammad Zarei
Barroso, Emma
Palomer, Xavier
Dai, Jianli
Rada, Patricia
Quesada-López, Tania
Escolà-Gil, Joan Carles
Cedó, Lidia
Mohammad Reza Zali
Molaei, Mahsa
Dabiri, Reza
Vázquez, Santiago
Pujol, Eugènia
Valverde, Ángela M.
Villarroya, Francesc
Liu, Yong
Wahli, Walter
Vázquez-Carrera, Manuel
Keywords: VLDLR
Issue Date: 2017
Source: Mohammad Zarei, Barroso, E., Palomer, X., Dai, J., Rada, P., Quesada-López, T., et al. (2018). Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease. Molecular Metabolism, 8, 117-131.
Series/Report no.: Molecular Metabolism
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.
ISSN: 2212-8778
DOI: 10.1016/j.molmet.2017.12.008
Rights: © 2017 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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