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2018

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cc-by-nc-nd (c) Zarei, Mohammad et al., 2018
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/121601

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

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https://doi.org/10.1016/j.molmet.2017.12.008

Resum

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.

Matèries

Malalties del fetge, Trastorns del metabolisme dels lípids

Matèries (anglès)

Liver diseases, Lipid metabolism disorders

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Col·leccions

Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Citació

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. Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease. _Molecular Metabolism_. 2018. Vol. 8, núm. 117-131. [consulta: 21 de gener de 2026]. ISSN: 2212-8778. [Disponible a: https://hdl.handle.net/2445/121601]

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