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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 5

miR-483 levels were decreased in hyperlipidemic mice and human subjects.

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miR-483 levels were decreased in hyperlipidemic mice and human subjects....
(A and B) Male and female C57BL/6 mice were fed an HFD or chow diet, and Ldlr-/- mice were fed an HFD for 6 weeks. (C) Correlation of serum levels of miR-483-5p and total cholesterol assessed by the Pearson correlation. (D) Serum was collected from humans (n = 179). Serum levels of total cholesterol and miR-483-5p were measured and correlated. (E and F) Humans (n = 179) were divided into 4 groups based on LDL-C levels: <100 mg/dL (optimal, n = 65, gray dots); 100–129 mg/dL (near/above optimal, n = 46, orange dots); 130–159 mg/dL (borderline high, n = 31, pink dots); and ≥160 mg/dL (high, n = 37, red dots). The correlation between serum levels of LDL-C and miR-483-5p is shown in E. Correlations between the optimal group with the other 3 subgroups (n = 111, 96, 102, respectively) are shown in F. ΔCT represents the difference between the cycle threshold of miR-483-5p and Cel-miR-39. In A and B, data are mean ± SEM from 8 mice per group. Normally distributed data were analyzed by 1-way ANOVA test with a Bonferroni’s post hoc test between 2 indicated groups. The correlation analysis was assessed by the Pearson method. *P < 0.05. miR, microRNA; HFD, high-fat diet; LDL-C, LDL-cholesterol.
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