PT  - JOURNAL ARTICLE
AU  - Na Wang
AU  - Lishu He
AU  - Hui Lin
AU  - Lunbo Tan
AU  - Yuan Sun
AU  - Xiaoying Zhang
AU  - A.H. Jan Danser
AU  - Hong S. Lu
AU  - Yongcheng He
AU  - Xifeng Lu
TI  - MicroRNA-148a Regulates Low-Density Lipoprotein Metabolism by Repressing the (Pro)renin Receptor
AID  - 10.1101/831529
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 831529
4099  - http://biorxiv.org/content/early/2019/11/05/831529.short
4100  - http://biorxiv.org/content/early/2019/11/05/831529.full
AB  - High 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.