Hepatic regulation of VLDL receptor by PPARß/d and FGF21 modulates non-alcoholic fatty liver disease.
Por:
Zarei M, Barroso E, Palomer FX, Dai J, Rada P, Quesada T, Escolà-Gil JC, Cedó L, Zali MR, Molaei M, Dabiri R, Vázquez S, Pujol E, Valverde ÁM, Villarroya-Gombau F, Liu Y, Wahli W and Vazquez M
Publicada:
1 feb 2018
Ahead of Print:
19 dic 2017
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)ß/d and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. METHODS: Studies were conducted in wild-type and Pparß/d-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 Pparß/d-null mice and in Pparß/d-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2a (eIF2a) 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 PPARß/d mRNA abundance and DNA-binding activity compared with control subjects. CONCLUSIONS: Overall, these findings provide new mechanisms by which PPARß/d and FGF21 regulate VLDLR levels and influence hepatic steatosis development.
Filiaciones:
Zarei M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Barroso E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Palomer FX:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Dai J:
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China
Rada P:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
Quesada T:
Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Department of Biochemistry and Molecular Biomedicine and IBUB, University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBEROBN)-Instituto de Salud Carlos III, Spain
Escolà-Gil JC:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain
Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
Cedó L:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain
Zali MR:
Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Molaei M:
Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Dabiri R:
lnternal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
Vázquez S:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Pujol E:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Valverde ÁM:
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC/UAM), Madrid, Spain
Villarroya-Gombau F:
Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Department of Biochemistry and Molecular Biomedicine and IBUB, University of Barcelona, Barcelona, Spain
Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBEROBN)-Instituto de Salud Carlos III, Spain
Liu Y:
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, Wuhan, China
Wahli W:
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore
INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France
Vazquez M:
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain
Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
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