| Autor: |
Mohammad Zarei, Emma Barroso, Xavier Palomer, Jianli Dai, Patricia Rada, Tania Quesada-López, Joan Carles Escolà-Gil, Lidia Cedó, Mohammad Reza Zali, Mahsa Molaei, Reza Dabiri, Santiago Vázquez, Eugènia Pujol, Ángela M. Valverde, Francesc Villarroya, Yong Liu, Walter Wahli, Manuel Vázquez-Carrera |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
Molecular Metabolism, Vol 8, Iss , Pp 117-131 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2212-8778 |
| DOI: |
10.1016/j.molmet.2017.12.008 |
| Popis: |
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)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Methods: Studies were conducted in wild-type and Pparβ/δ-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 Pparβ/δ-null mice and in Pparβ/δ-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) 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 PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects. Conclusions: Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development. Keywords: VLDLR, PPAR, FGF21, ATF4, ER stress |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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