Activation of PPAR-δ induces microRNA-100 and decreases the uptake of very low-density lipoprotein in endothelial cells

Br J Pharmacol. 2015 Aug;172(15):3728-36. doi: 10.1111/bph.13160. Epub 2015 Jun 26.

Abstract

Background and purpose: Increased level of very low-density lipoprotein (VLDL) is a key feature of the metabolic syndrome and is associated with cardiovascular diseases. PPAR-δ agonists play a protective role in lipid metabolism and vascular function. In this study, we aimed to investigate the role of PPAR-δ in the uptake of VLDL in endothelial cells and its underlying mechanism(s).

Experimental approach: Uptake of VLDL in HUVECs was assessed by Dil-fluorescent labelling of VLDL. Levels of VLDL receptor mRNA and microRNA (miR-100) were detected by quantitative PCR. The target genes of miR-100 were predicted using bioinformatics analysis. 3'-Untranslated region (3'-UTR) luciferase reporter and Argonaute 1 pull-down assays were used to validate the target of miR-100.

Key results: PPAR-δ agonist GW501516 decreased uptake of VLDL and expression of VLDL receptor at mRNA and protein levels. GW501516 inhibited the luciferase reporter activity of the 3'-UTR of VLDL receptor. VLDL receptor was a direct target of miR-100. miR-100 was significantly increased by GW501516 in HUVECs. Transfection of a miR-100 mimic decreased the mRNA and protein levels of VLDL receptor and uptake of VLDL. Furthermore, a miR-100 inhibitor abolished the inhibitory effect of PPAR-δ on VLDL receptor expression and VLDL uptake.

Conclusions and implications: In endothelial cells, activation of PPAR-δ decreased VLDL receptor expression and VLDL uptake via the induction of miR-100. These results provided a novel mechanism for the vascular protective effect of PPAR-δ agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Humans
  • Lipoproteins, VLDL / metabolism*
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / metabolism*
  • PPAR delta / agonists
  • PPAR delta / physiology*
  • Receptors, LDL / antagonists & inhibitors
  • Receptors, LDL / biosynthesis
  • Thiazoles / pharmacology

Substances

  • GW 501516
  • Lipoproteins, VLDL
  • MIRN100 microRNA, human
  • MicroRNAs
  • PPAR delta
  • Receptors, LDL
  • Thiazoles
  • VLDL receptor