MicroRNA-148a regulates low-density lipoprotein metabolism by repressing the (pro)renin receptor

• DOI: 10.1371/journal.pone.0225356
• Publication Date: 2020-05-21T17:40:02Z
• Authors: Na Wang; Lishu He; Hui Lin; Lunbo Tan; Yuan Sun; Xiaoying Zhang; A. H. Jan Danser; Hong S. Lu; Yongcheng He; Xifeng Lu
• Keywords: 0301 basic medicine; Vacuolar Proton-Translocating ATPases; Science; EMC OR-01; Q; R; Receptors, Cell Surface; Hep G2 Cells; Lipoproteins, LDL; MicroRNAs; 03 medical and health sciences; HEK293 Cells; Receptors, LDL; Medicine; Humans; Research Article

AbstractHigh plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDLR regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we identified the (pro)renin receptor [(P)RR] as a novel regulator of LDL metabolism, which regulates LDLR degradation and hence its protein abundance and activity. In silicon analysis suggests that the (P)RR is a target of miR-148a. In this study we determined whether miR-148a could regulate LDL metabolism by regulating (P)RR expression in HepG2 and Huh7 cells. We found that miR-148a suppressed (P)RR expression by binding to the 3’-untranslated regions (3’-UTR) of (P)RR mRNA. Mutating the binding sites for miR-148a in the 3’-UTR of (P)RR mRNA abolished the inhibitory effects of miR-148a on (P)RR expression. In line with our recent findings, reduced (P)RR expression resulted in decreased cellular LDL uptake, likely as a consequence of decreased LDLR protein abundance. Overexpressing the (P)RR prevented miR-148a-induced reduction in LDLR abundance and cellular LDL uptake. Our study supports a new concept that miR-148a is a regulator of (P)RR expression. By reducing (P)RR abundance, miR-148a decreases LDLR protein abundance and consequently cellular LDL uptake.