Zarei, MohammadBarroso Fernández, EmmaPalomer Tarridas, Francesc XavierDai, JianliRada, PatriciaQuesada López, Tania PalomaEscolà Gil, Joan CarlesCedó Giné, LídiaZali, Mohammad RezaMolaei, MahsaDabiri, RezaVázquez Cruz, SantiagoPujol Bech, EugèniaValverde, Ángela M.Villarroya i Gombau, FrancescLiu, YongWahli, WalterVázquez Carrera, Manuel2018-04-172018-04-1720182212-8778https://hdl.handle.net/2445/121601OBJECTIVE: 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)beta/delta and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. METHODS: Studies were conducted in wild-type and Pparbeta/delta-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 Pparbeta/delta-null mice and in Pparbeta/delta-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2alpha (eIF2alpha) 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 PPARbeta/delta mRNA abundance and DNA-binding activity compared with control subjects. CONCLUSIONS: Overall, these findings provide new mechanisms by which PPARbeta/delta and FGF21 regulate VLDLR levels and influence hepatic steatosis development.15 p.application/pdfengcc-by-nc-nd (c) Zarei, Mohammad et al., 2018http://creativecommons.org/licenses/by-nc-nd/3.0/esMalalties del fetgeTrastorns del metabolisme dels lípidsLiver diseasesLipid metabolism disordersinfo:eu-repo/semantics/article6763672018-04-17info:eu-repo/semantics/openAccess29289645