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.

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Published in PLOS ONE, v. 15, no. 5, 0225356, p. 1-14.

© 2020 Wang et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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This work is supported by National Natural Science Foundation of China (grant no. 81870605, 81800383, 81500667) and Shenzhen Municipal Science and Technology Innovation Council (grant no. JCYJ20160307160819191).

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S1 Fig. Small interfering RNA targeting 3’-UTR regions of human LDLR effectively reduces luciferase activity. https://doi.org/10.1371/journal.pone.0225356.s001

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S2 Fig. MiR-148a does not affect LDLR and ABCA1 expression under lipid-deficient condition. https://doi.org/10.1371/journal.pone.0225356.s002

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S3 Fig. MiR-148b regulates (P)RR expression by targeting its 3’-UTR sequences. https://doi.org/10.1371/journal.pone.0225356.s003

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S4 Fig. MiR-148a reduces SORT1 protein abundance but does not affect its transcript levels. https://doi.org/10.1371/journal.pone.0225356.s004

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S5 Fig. https://doi.org/10.1371/journal.pone.0225356.s005

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S1 Table. List of miRNA, siRNA and primers used in the current study. https://doi.org/10.1371/journal.pone.0225356.s006