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2018

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cc-by-nc-nd (c) Zarei, Mohammad et al., 2018
Please use this identifier to cite or link to this item: 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

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)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.

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Malalties del fetge, Trastorns del metabolisme dels lípids

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Liver diseases, Lipid metabolism disorders

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

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ZAREI, Mohammad, et al. Hepatic regulation of VLDL receptor by PPARbeta/delta and FGF21 modulates non-alcoholic fatty liver disease. Molecular Metabolism. 2018. Vol. 8, num. 117-131. ISSN 2212-8778. [consulted: 14 of August of 2026]. Available at: https://hdl.handle.net/2445/121601

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