Título:
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Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease
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Autor/a:
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Zarei, Mohammad; Barroso, Emma; Palomer, Xavier; Dai, Jianli; Rada, Patricia; Quesada-López, Tania; Escolà-Gil, Joan Carles; Cedó, Lídia; Zali, Mohammad Reza; Molaei, Mahsa; Dabiri, Reza; Vázquez, Santiago; Pujol Bech, Eugenia; Valverde, Ángela M.; Villarroya, Francesc; Liu, Yong; Wahli, Walter; Vázquez-Carrera, Manuel; Universitat Autònoma de Barcelona
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Abstract:
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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. 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. 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. Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development. |
Materia(s):
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-VLDLR -PPAR -FGF21 -ATF4 -ER stress -ATF4, activating transcription factor 4 -Chop, C/EBP homologous protein -Eif2α, eukaryotic translation initiation factor 2α -FGF21, fibroblast growth factor 21 -HFD, high-fat diet -HRI, heme-regulated eIF2α kinase -NAFLD, non-alcoholic fatty liver disease -PPAR, peroxisome proliferator-activated receptor |
Derechos:
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open access
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https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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Article |
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Uri:
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https://ddd.uab.cat/record/190659
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