Title:
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Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease
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Author:
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Zarei, Mohammad; Barroso Fernández, Emma; Palomer Tarridas, Francesc Xavier; Dai, Jianli; Rada, Patricia; Quesada López, Tania Paloma; Escolà i 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
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Other authors:
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Universitat de Barcelona |
Abstract:
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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. |
Subject(s):
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-Malalties del fetge -Trastorns del metabolisme dels lípids -Liver diseases -Lipid metabolism disorders |
Rights:
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cc-by-nc-nd (c) Zarei, Mohammad et al., 2018
http://creativecommons.org/licenses/by-nc-nd/3.0/es |
Document type:
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Article Article - Published version |
Published by:
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Elsevier GmbH
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