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microRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production
Jianjie Dong, … , Sotirios Tsimikas, John Y.J. Shyy
Jianjie Dong, … , Sotirios Tsimikas, John Y.J. Shyy
Published October 29, 2020
Citation Information: JCI Insight. 2020;5(23):e143812. https://doi.org/10.1172/jci.insight.143812.
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Research Article Metabolism Vascular biology

microRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production

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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects cholesterol homeostasis by targeting hepatic LDL receptor (LDLR) for lysosomal degradation. Clinically, PCSK9 inhibitors effectively reduce LDL-cholesterol (LDL-C) levels and the incidence of cardiovascular events. Because microRNAs (miRs) are integral regulators of cholesterol homeostasis, we investigated the involvement of miR-483 in regulating LDL-C metabolism. Using in silico analysis, we predicted that miR-483-5p targets the 3′-UTR of PCSK9 mRNA. In HepG2 cells, miR-483-5p targeted the PCSK9 3′-UTR, leading to decreased PCSK9 protein and mRNA expression, increased LDLR expression, and enhanced LDL-C uptake. In hyperlipidemic mice and humans, serum levels of total cholesterol and LDL-C were inversely correlated with miR-483-5p levels. In mice, hepatic miR-483 overexpression increased LDLR levels by targeting Pcsk9, with a significant reduction in plasma total cholesterol and LDL-C levels. Mechanistically, the cholesterol-lowering effect of miR-483-5p was significant in mice receiving AAV8 PCSK9-3′-UTR but not Ldlr-knockout mice or mice receiving AAV8 PCSK9-3′-UTR (ΔBS) with the miR-483-5p targeting site deleted. Thus, exogenously administered miR-483 or similarly optimized compounds have potential to ameliorate hypercholesterolemia.

Authors

Jianjie Dong, Ming He, Jie Li, Ariane Pessentheiner, Chen Wang, Jin Zhang, Yameng Sun, Wei-Ting Wang, Yuqing Zhang, Junhui Liu, Shen-Chih Wang, Po-Hsun Huang, Philip L.S.M. Gordts, Zu-Yi Yuan, Sotirios Tsimikas, John Y.J. Shyy

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Figure 2

miR-483 regulates PCSK9 via posttranslational mechanism.

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miR-483 regulates PCSK9 via posttranslational mechanism.
(A and D) The a...
(A and D) The animals were used as described in Figure 1. The hepatic Pcsk9 mRNA levels (A), ELISA detection of serum levels of PCSK9 (A), and hepatic levels of miR-191, -222, -224, and -483 (D) are shown. (B) Previously reported (blue lines) or newly predicted (green lines) miRs that bind to the hPCSK9-3′-UTR are shown. (C and E) HepG2 cells were transfected with pre–miR-222 mimic (222), pre–miR-224 mimic (224), pre–miR-483 mimic (483), pre–miR-191 mimic (191), pre–miR-1912 mimic (1912), pre–miR-1295b mimic (1295b), or scramble miR control (Ctrl). In C, cells were cotransfected with Luc-PCSK9-3′-UTR reporter. Luciferase activity was measured with pRL-TK activity as a transfection control. In E, protein levels of PCSK9 and LDLR were determined by Western blot analysis; α-tubulin was a loading control. In A and D, data are mean ± SEM from 6–8 mice per group. Normally distributed data were analyzed by 2-tailed Student’s t test with Welch correction between 2 groups. In C and E, data are mean ± SEM from 3–4 independent experiments. Non-normally distributed data were analyzed using Mann-Whitney U test between indicated group and control. *P < 0.05 vs. AAV8-PCSK9 or Ctrl. miR, microRNA; PCSK9, proprotein convertase subtilisin/kexin type 9; HepG2, human hepatocellular carcinoma; LDLR, LDL receptor.

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