Pharmacological PPARβ/δ activation upregulates VLDLR in hepatocytes
Clin Investig Arterioscler. 2019 May-Jun;31(3):111-118.
doi: 10.1016/j.arteri.2019.01.004.
Epub 2019 Apr 13.
[Article in
English,
Spanish]
Affiliations
- 1 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, Spain; Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain.
- 2 Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Spain; Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain; Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
- 3 Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore; INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France.
- 4 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, Spain; Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain. Electronic address: mvazquezcarrera@ub.edu.
Abstract
The very low-density lipoprotein receptor (VLDLR) plays an important function in the control of serum triglycerides and in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the role of peroxisome proliferator-activated receptor (PPAR)β/δ activation in hepatic VLDLR regulation. Treatment of mice fed a high-fat diet with the PPARβ/δ agonist GW501516 increased the hepatic expression of Vldlr. Similarly, exposure of human Huh-7 hepatocytes to GW501516 increased the expression of VLDLR and triglyceride accumulation, the latter being prevented by VLDLR knockdown. Finally, treatment with another PPARβ/δ agonist increased VLDLR levels in the liver of wild-type mice, but not PPARβ/δ-deficient mice, confirming the regulation of hepatic VLDLR by this nuclear receptor. Our results suggest that upregulation of hepatic VLDLR by PPARβ/δ agonists might contribute to the hypolipidemic effect of these drugs by increasing lipoprotein delivery to the liver. Overall, these findings provide new effects by which PPARβ/δ regulate VLDLR levels and may influence serum triglyceride levels and NAFLD development.
Keywords:
EHGNA; NAFLD; PPAR; VLDLR.
Copyright © 2019 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.
MeSH terms
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Animals
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Cells, Cultured
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Disease Models, Animal
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Hepatocytes / metabolism*
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Humans
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Hypolipidemic Agents / pharmacology
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Liver / pathology
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Male
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Mice
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Mice, Knockout
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Non-alcoholic Fatty Liver Disease / pathology*
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PPAR delta / agonists*
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PPAR delta / genetics
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PPAR-beta / agonists*
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PPAR-beta / genetics
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Receptors, LDL / genetics*
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Thiazoles / pharmacology
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Triglycerides / blood
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Up-Regulation
Substances
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GW 501516
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Hypolipidemic Agents
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PPAR delta
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PPAR-beta
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Receptors, LDL
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Thiazoles
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Triglycerides
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VLDL receptor