Hepatic regulation of VLDL receptor by PPAR beta/delta and FGF21 modulates non-alcoholic fatty liver disease
Por:
Zarei, M, Barroso, E, Palomer, X, Dai, JL, Rada, P, Quesada-Lopez, T, Escola-Gil, JC, Cedo, L, Zali, MR, Molaei, M, Dabiri, R, Vazquez, S, Pujol, E, Valverde, AM, Villarroya, F, Liu, Y, Wahli, W, Vazquez-Camera, M
Publicada:
1 feb 2018
Resumen:
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 Ppar beta/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 Ppar beta/delta-null mice and in Ppar beta/delta-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2 alpha (e1F2 alpha) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived2)-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 PPAR beta/delta mRNA abundance and DNA-binding activity compared with control subjects.
Conclusions: Overall, these findings provide new mechanisms by which PPAR beta/delta and FGF21 regulate VLDLR levels and influence hepatic steatosis development. 2017 The Authors. Published by Elsevier GmbH.
Filiaciones:
Zarei, M:
Univ Barcelona, Inst Biomed, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Hosp St Joan de Deu, Inst Res, Barcelona, Spain
Barroso, E:
Univ Barcelona, Inst Biomed, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Hosp St Joan de Deu, Inst Res, Barcelona, Spain
Palomer, X:
Univ Barcelona, Inst Biomed, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Hosp St Joan de Deu, Inst Res, Barcelona, Spain
Dai, JL:
Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Nutr & Metab,Inst Nutr Sci, Shanghai, Peoples R China
Rada, P:
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Inst Invest Biomed Alberto Sols CSIC UAM, Madrid, Spain
Quesada-Lopez, T:
Hosp St Joan de Deu, Inst Res, Barcelona, Spain
Univ Barcelona, Dept Biochem & Mol Biomed, Barcelona, Spain
Univ Barcelona, IBUB, Barcelona, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Physiopathol Obes & Nutr C, Barcelona, Spain
Escola-Gil, JC:
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Inst Invest Biomed IIB St Pau, Barcelona, Spain
Univ Autbnoma Barcelona, Dept Bioquim & Biol Mol, Barcelona, Spain
Cedo, L:
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Inst Invest Biomed IIB St Pau, Barcelona, Spain
Zali, MR:
Shahid Beheshti Univ Med Sci, Res Inst Gastroenterol & Liver Dis, Gastroenterol & Liver Dis Res Ctr, Tehran, Iran
Molaei, M:
Shahid Beheshti Univ Med Sci, Res Inst Gastroenterol & Liver Dis, Gastroenterol & Liver Dis Res Ctr, Tehran, Iran
Dabiri, R:
Semnan Univ Med Sci, Dept Internal Med, Semnan, Iran
Vazquez, S:
Univ Barcelona, Inst Biomed, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona, Spain
Pujol, E:
Univ Barcelona, Inst Biomed, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona, Spain
Valverde, AM:
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Inst Invest Biomed Alberto Sols CSIC UAM, Madrid, Spain
Villarroya, F:
Hosp St Joan de Deu, Inst Res, Barcelona, Spain
Univ Barcelona, Dept Biochem & Mol Biomed, Barcelona, Spain
Univ Barcelona, IBUB, Barcelona, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Physiopathol Obes & Nutr C, Barcelona, Spain
Liu, Y:
Wuhan Univ, Inst Adv Studies, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan, Peoples R China
Wahli, W:
Univ Lausanne, Ctr Integrat Genom, Lausanne, Switzerland
Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore 308232, Singapore
INRA ToxAlim, UMR1331, Chemin Tournefeuille, Toulouse, France
Vazquez-Camera, M:
Univ Barcelona, Inst Biomed, Fac Pharm & Food Sci, Dept Pharmacol Toxicol & Therapeut Chem, Barcelona, Spain
Inst Salud Carlos III, Spanish Biomed Res Ctr Diabet & Associated Metab, Barcelona, Spain
Hosp St Joan de Deu, Inst Res, Barcelona, Spain
Gold, Green Published
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