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Theranostics 2020; 10(9):3952-3966. doi:10.7150/thno.39578 This issue Cite

Research Paper

Activation of microRNA-378a-3p biogenesis promotes hepatic secretion of VLDL and hyperlipidemia by modulating ApoB100-Sortilin1 axis

Tianpeng Zhang^1*, Hongtao Shi^2*, Ningning Liu¹, Jing Tian², Xiaoling Zhao³, Clifford J. Steer¹, Qinghua Han^2✉, Guisheng Song^1✉

1. Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455
2. Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China 030001
3. MC Lab, South San Francisco, CA 94080
*Tianpeng Zhang and Hongtao Shi equally contributed to this manuscript.

✉ Corresponding authors: Guisheng Song, Ph.D., 516 Delaware Street SE, Minneapolis MN 55455, Tel: 1-61-924-9961, E-mail: gsongedu Or Qinghua Han, M.D., Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China, Email: sygqhcom More

Abstract

Rationale: Hyperlipidemia is a major risk factor of atherosclerosis and cardiovascular diseases (CVD). As a standard-of-care approach for hyperlipidemia, statins only reduce the risk of coronary artery disease by 20-40%, underscoring the importance of identifying molecular pathways for the design of drugs against this disorder. Alterations in microRNA (miRNA) expression have been reported in patients with hyperlipidemia and CVD. This study was designed to determine the mechanism of dysregulated miR-378a-3p under the status of hyperlipidemia and evaluate how miR-378a-3p regulates hepatic secretion of VLDL.

Methods: Wild-type mice kept on a high fat diet were injected with miR-378a-3p inhibitor or a mini-circle expression system containing miR-378a precursor to study loss and gain-of functions of miR-378a-3p. Mice were treated with Triton WR1339 and ³⁵S-methionine/cysteine to determine the effect of miR-378a-3p on hepatic secretion of VLDL. Database mining, luciferase assay, and ChIP (chromatin immunoprecipitation) were used to study the mechanism of dysregulated miR-378a-3p biogenesis.

Results: miR-378a-3p expression is significantly increased in livers of hyperlipidemic mice. Sort1 (sortilin 1) was identified as a direct target of miR-378a-3p. By inhibiting the function of sortilin 1 as a transmembrane trafficking receptor, miR-378a-3p stabilized ApoB100 and promoted ApoB100 secretion in vitro. Liver-specific expression of miR-378a-3p stabilized ApoB100 and facilitated hepatic secretion of VLDL, which subsequently increased levels of VLDL/LDL cholesterol as well as triglycerides. In contrast, antagonizing miR-378a-3p using its inhibitor increased hepatic expression of Sort1 and reduced hepatic export of VLDL with its consequent effects of serum lipid levels. Additional knockdown of up-regulated Sort1 in livers of mice offset the effects of miR-378a-3p inhibitor, suggesting that Sort1 was indispensable for miR-378a-3p to promote secretion of VLDL and thereby high levels of circulating VLDL/LDL cholesterol and triglycerides. Furthermore, oncogenic E2F1 (E2F transcription factor 1) was identified as a transcriptional activator of miR-378a-3p. E2f1 knockdown, through reducing miR-378a-3p, impaired secretion of VLDL and reduced levels of VLDL/LDL cholesterol and triglycerides.

Conclusions: This study defines a novel pathway of E2F1-miR-378a-3p-SORT1-ApoB100 that controls levels of circulating VLDL/LDL cholesterol and triglycerides by modulating degradation and secretion of ApoB100, and suggests the use of miR-378a-3p as a potential therapeutic target for dyslipidemia.

Keywords: microRNA, hyperlipidemia, lipoprotein

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