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

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)beta/delta and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. ME...

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Autores: Zarei, Mohammad, Barroso Fernández, Emma, Palomer Tarridas, Francesc Xavier, Dai, Jianli, Rada, Patricia, Quesada López, Tania Paloma, Escolà Gil, Joan Carles, Cedó Giné, Lídia, Zali, Mohammad Reza, Molaei, Mahsa, Dabiri, Reza, Vázquez Cruz, Santiago, Pujol Bech, Eugènia, Valverde, Ángela M., Villarroya i Gombau, Francesc, Liu, Yong, Wahli, Walter, Vázquez Carrera, Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/121601
Acceso en línea:https://hdl.handle.net/2445/121601
Access Level:acceso abierto
Palabra clave:Malalties del fetge
Trastorns del metabolisme dels lípids
Liver diseases
Lipid metabolism disorders
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spelling Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver diseaseZarei, 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, ManuelMalalties del fetgeTrastorns del metabolisme dels lípidsLiver diseasesLipid metabolism disordersOBJECTIVE: 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.Elsevier GmbH2018201820182018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion15 p.application/pdfhttps://hdl.handle.net/2445/121601Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.molmet.2017.12.008Molecular Metabolism, 2018, vol. 8, p. 117-131https://doi.org/10.1016/j.molmet.2017.12.008cc-by-nc-nd (c) Zarei, Mohammad et al., 2018http://creativecommons.org/licenses/by-nc-nd/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1216012026-05-29T05:05:01Z
dc.title.none.fl_str_mv Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
title Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
spellingShingle Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
Zarei, Mohammad
Malalties del fetge
Trastorns del metabolisme dels lípids
Liver diseases
Lipid metabolism disorders
title_short Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
title_full Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
title_fullStr Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
title_full_unstemmed Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
title_sort Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
dc.creator.none.fl_str_mv Zarei, Mohammad
Barroso Fernández, Emma
Palomer Tarridas, Francesc Xavier
Dai, Jianli
Rada, Patricia
Quesada López, Tania Paloma
Escolà Gil, Joan Carles
Cedó Giné, Lídia
Zali, Mohammad Reza
Molaei, Mahsa
Dabiri, Reza
Vázquez Cruz, Santiago
Pujol Bech, Eugènia
Valverde, Ángela M.
Villarroya i Gombau, Francesc
Liu, Yong
Wahli, Walter
Vázquez Carrera, Manuel
author Zarei, Mohammad
author_facet Zarei, Mohammad
Barroso Fernández, Emma
Palomer Tarridas, Francesc Xavier
Dai, Jianli
Rada, Patricia
Quesada López, Tania Paloma
Escolà Gil, Joan Carles
Cedó Giné, Lídia
Zali, Mohammad Reza
Molaei, Mahsa
Dabiri, Reza
Vázquez Cruz, Santiago
Pujol Bech, Eugènia
Valverde, Ángela M.
Villarroya i Gombau, Francesc
Liu, Yong
Wahli, Walter
Vázquez Carrera, Manuel
author_role author
author2 Barroso Fernández, Emma
Palomer Tarridas, Francesc Xavier
Dai, Jianli
Rada, Patricia
Quesada López, Tania Paloma
Escolà Gil, Joan Carles
Cedó Giné, Lídia
Zali, Mohammad Reza
Molaei, Mahsa
Dabiri, Reza
Vázquez Cruz, Santiago
Pujol Bech, Eugènia
Valverde, Ángela M.
Villarroya i Gombau, Francesc
Liu, Yong
Wahli, Walter
Vázquez Carrera, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties del fetge
Trastorns del metabolisme dels lípids
Liver diseases
Lipid metabolism disorders
topic Malalties del fetge
Trastorns del metabolisme dels lípids
Liver diseases
Lipid metabolism disorders
description 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)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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/121601
url https://hdl.handle.net/2445/121601
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.molmet.2017.12.008
Molecular Metabolism, 2018, vol. 8, p. 117-131
https://doi.org/10.1016/j.molmet.2017.12.008
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Zarei, Mohammad et al., 2018
http://creativecommons.org/licenses/by-nc-nd/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Zarei, Mohammad et al., 2018
http://creativecommons.org/licenses/by-nc-nd/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 15 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier GmbH
publisher.none.fl_str_mv Elsevier GmbH
dc.source.none.fl_str_mv Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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