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

• Published in: British journal of pharmacology Vol. 172; no. 15; pp. 3728 - 3736
• Main Authors: Fang, Xi, Fang, Li, Liu, Ao, Wang, Xiaohong, Zhao, Beilei, Wang, Nanping
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Ltd 01.08.2015
• Subjects: 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; Research Papers; Thiazoles - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13160

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.