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Vol. 31. Issue 3.
Pages 111-118 (May - June 2019)
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Vol. 31. Issue 3.
Pages 111-118 (May - June 2019)
Original article
Pharmacological PPARβ/δ activation upregulates VLDLR in hepatocytes
La activación de PPARβ/δ aumenta los niveles de VLDLR en hepatocitos
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Mohammad Zareia,b,c, Emma Barrosoa,b,c, Xavier Palomera,b,c, Joan Carles Escolà-Gilb,d,e, Lidia Cedób,d,e, Walter Wahlif,g,h, Manuel Vázquez-Carreraa,b,c,
Corresponding author
mvazquezcarrera@ub.edu

Corresponding author.
a 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
b Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III, Spain
c Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain
d Institut d’Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain
e Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain
f Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
g Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
h INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex, France
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Table 1. Primer sequences used for real-time RT-PCR.
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:
VLDLR
PPAR
NAFLD
Abbreviations:
HFD
NAFLD
PPAR
Resumen

El receptor de las lipoproteínas de muy baja densidad (VLDLR) desempeña una función muy importante en el control de los niveles de triglicéridos séricos y en el desarrollo de la enfermedad del hígado graso no alcohólico (EHGNA). En este estudio hemos investigado el papel de la activación del receptor activado por los proliferadores peroxisómicos (PPAR)β/δ en la regulación hepática del VLDLR. El tratamiento de ratones alimentados con una dieta rica en grasas con el agonista PPARβ/δ GW501516 aumentó la expresión hepática de Vldlr. Asimismo, la exposición de hepatocitos humanos Huh-7 a GW501516 aumentó la expresión de VLDLR y la acumulación de triglicéridos, siendo este ultimo aumento evitado por el knockdown de VLDLR. Finalmente, el tratamiento con otro agonista PPARβ/δ incrementó los niveles de VLDLR en el hígado de ratones wild-type, pero no en el de ratones deficientes en PPARβ/δ, confirmando la regulación del VLDLR hepático por este receptor. En conjunto, nuestros resultados proporcionan un nuevo efecto por el que PPARβ/δ regula los niveles de VLDLR y puede influenciar los niveles de triglicéridos séricos así como el desarrollo de la EHGNA.

Palabras clave:
VLDLR
PPAR
EHGNA

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