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

Background and PurposeIncreased level of very low-density lipoprotein (VLDL) is a key feature of the metabolic syndrome and is associated with cardiovascular diseases. PPAR- agonists play a protective role in lipid metabolism and vascular function. In this study, we aimed to investigate the role of PPAR- in the uptake of VLDL in endothelial cells and its underlying mechanism(s). Experimental ApproachUptake 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 ResultsPPAR- 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- on VLDL receptor expression and VLDL uptake. Conclusions and ImplicationsIn endothelial cells, activation of PPAR- 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- agonists.