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

Na Wang,Hong S Lu,Lishu He,Xiaoying Zhang,Yongcheng He,A H Jan Danser,Lunbo Tan,Xifeng Lu,Hui Lin,Yuan Sun

doi:10.1371/journal.pone.0225356

Abstract

High plasma LDL cholesterol (LDL-c) concentration is a major risk factor for atherosclerosis. Hepatic LDL receptor (LDLR) regulates LDL metabolism, and thereby plasma LDL-c concentration. Recently, we have 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 silico 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 the (P)RR mRNA. Mutating the binding sites for miR-148a in the 3’-UTR of (P)RR mRNA completely 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.

Highlights

Elevated plasma LDL cholesterol (LDL-c) level is a major risk factor for cardiovascular diseases (CVD), a leading cause of world-wide death
We found that miR-148a reduces LDL receptor (LDLR) protein abundance and cellular LDL uptake
To rule out the possibility that the cells we used were contaminated with other cells, such as HeLa, we screened 19 short tandem repeat loci and the gender determining locus to determine their identity and confirmed that HepG2 and Huh7 cells used in the current study are correct cell lines

Summary

Introduction

Elevated plasma LDL cholesterol (LDL-c) level is a major risk factor for cardiovascular diseases (CVD), a leading cause of world-wide death. Plasma LDL is mainly cleared by the LDLR in the liver. Genetic mutations resulting in defective LDLR functions are associated with elevated plasma LDL-c levels and increased risks for CVD [1].

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Results

Conclusion