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Title

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

AuthorsZarei, Mohammad; Barroso, Emma; Palomer, Xavier; Dai, Jianli; Rada, Patricia; Quesada-López, Tania; Escolà-Gil, Joan Carles; Cedó, Lídia; Reza Zali, Mohammad; Molaei, Mahsa; Dabiri, Reza; Vázquez, Santiago; Pujol, Eugènia; Valverde, Ángela M.; Villarroya, Francesc; Liu, Yong; Wahli, Walter; Vázquez-Carrera, Manuel
Issue DateFeb-2018
PublisherElsevier
CitationMolecular Metabolism 8: 117-131 (2018)
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)b/d and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. [Methods] Studies were conducted in wild-type and Pparb/d-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 Pparb/d-null mice and in Pparb/d-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2a (eIF2a) 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 PPARb/d mRNA abundance and DNA-binding activity compared with control subjects. [Conclusions]: Overall, these findings provide new mechanisms by which PPARb/d and FGF21 regulate VLDLR levels and influence hepatic steatosis development.
Publisher version (URL)https://doi.org/10.1016/j.molmet.2017.12.008
URIhttp://hdl.handle.net/10261/176870
DOI10.1016/j.molmet.2017.12.008
E-ISSN2212-8778
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