Pharmacological PPARβ/δ activation upregulates VLDLR in hepatocytes

Clin Investig Arterioscler. May-Jun 2019;31(3):111-118. doi: 10.1016/j.arteri.2019.01.004. Epub 2019 Apr 13.
[Article in English, Spanish]

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.

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Hepatocytes / metabolism*
  • Humans
  • Hypolipidemic Agents / pharmacology
  • Liver / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / pathology*
  • PPAR delta / agonists*
  • PPAR delta / genetics
  • PPAR-beta / agonists*
  • PPAR-beta / genetics
  • Receptors, LDL / genetics*
  • Thiazoles / pharmacology
  • Triglycerides / blood
  • Up-Regulation

Substances

  • GW 501516
  • Hypolipidemic Agents
  • PPAR delta
  • PPAR-beta
  • Receptors, LDL
  • Thiazoles
  • Triglycerides
  • VLDL receptor