serval:BIB_4C931839E09D
Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease.
10.1016/j.molmet.2017.12.008
000429084900011
29289645
Zarei
M.
author
Barroso
E.
author
Palomer
X.
author
Dai
J.
author
Rada
P.
author
Quesada-López
T.
author
Escolà-Gil
J.C.
author
Cedó
L.
author
Zali
M.R.
author
Molaei
M.
author
Dabiri
R.
author
Vázquez
S.
author
Pujol
E.
author
Valverde
Á.M.
author
Villarroya
F.
author
Liu
Y.
author
Wahli
W.
author
Vázquez-Carrera
M.
author
article
2018-02
Molecular metabolism
2212-8778
2212-8778
journal
8
117-131
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.
Activating Transcription Factor 4/genetics
Activating Transcription Factor 4/metabolism
Animals
Cell Line, Tumor
Female
Fibroblast Growth Factors/genetics
Fibroblast Growth Factors/metabolism
Humans
Liver/metabolism
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease/metabolism
PPAR delta/genetics
PPAR delta/metabolism
PPAR-beta/genetics
PPAR-beta/metabolism
Receptors, LDL/genetics
Receptors, LDL/metabolism
Signal Transduction
eIF-2 Kinase/genetics
eIF-2 Kinase/metabolism
ATF4
ER stress
FGF21
PPAR
VLDLR
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
University of Lausanne
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