1. Hepatic regulation of VLDL receptor by PPARβ/δ and FGF21 modulates non-alcoholic fatty liver disease
- Author
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Zarei, Mohammad, Barroso, Emma, Palomer, Xavier, Dai, Jianli, Rada, Patricia, Quesada-López, Tania, Escolà-Gil, Joan Carles, Cedó, Lídia, Reza Zali, Mohammad, Molaei, Mahsa, Dabiri, Reza, Vázquez, Santiago, Pujol, Eugènia, Valverde, Ángela M., Villarroya, Francesc, Liu, Yong, Wahli, Walter, Vázquez-Carrera, Manuel, Universitat Autònoma de Barcelona (UAB), Instituto de Salud Carlos III [Madrid] (ISC), Hospital Sant Joan de Déu, University of Chinese Academy of Sciences, CAS (UCAS), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBEROBN), Institut d'Investigacions Biomèdiques August Pi i Sunyer, Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, Semnan University of Medical Sciences, Partenaires INRAE, Wuhan University, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Vázquez-Carrera, Manuel, Lee Kong Chian School of Medicine (LKCMedicine), Ministerio de Economía y Competitividad (España), European Commission, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España), Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Instituto de Salud Carlos III, Nanyang Technological University, Région Midi-Pyrénées, and Consejo Nacional de Ciencia y Tecnología (México) more...
- Subjects
Male ,HFD, high-fat diet ,NAFLD, non-alcoholic fatty liver disease ,lcsh:Internal medicine ,ATF4, activating transcription factor 4 ,HRI, heme-regulated eIF2α kinase ,[SDV]Life Sciences [q-bio] ,FGF21, fibroblast growth factor 21 ,PPAR, peroxisome proliferator-activated receptor ,PPAR ,ER stress ,VLDLR ,Mice ,eIF-2 Kinase ,FGF21 ,Non-alcoholic Fatty Liver Disease ,Cell Line, Tumor ,eIF2α, eukaryotic translation initiation factor 2α ,Animals ,Humans ,Activating Transcription Factor 4/genetics ,Activating Transcription Factor 4/metabolism ,Female ,Fibroblast Growth Factors/genetics ,Fibroblast Growth Factors/metabolism ,Liver/metabolism ,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 ,PPAR delta ,lcsh:RC31-1245 ,PPAR-beta ,Chop, C/EBP homologous protein ,Activating Transcription Factor 4 ,Fibroblast Growth Factors ,Liver ,Receptors, LDL ,Original Article - Abstract
[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)b/d and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. [Methods] Studies were conducted in wild-type and Pparb/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 Pparb/d-null mice and in Pparb/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 PPARb/d mRNA abundance and DNA-binding activity compared with control subjects. [Conclusions]: Overall, these findings provide new mechanisms by which PPARb/d and FGF21 regulate VLDLR levels and influence hepatic steatosis development., This study was partly supported by funds from the Spanish Ministry of the Economy and Competitiveness (SAF2015-64146-R to MVC, SAF2014-55725 to FV, and SAF2015-65267-R to AMV) and European Union ERDF funds. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn) are Carlos III Health Institute projects. WW is supported by Start-Up Grants from the Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, and by the Région Midi-Pyrénées, France, and TQL is supported by a CONACyT (National Council for Science and Technology in Mexico) Ph.D. scholarship. more...
- Published
- 2018
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