MiR-486 regulates cholesterol efflux by targeting HAT1
MiR-486 regulates cholesterol efflux by targeting HAT1
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DOI：
10.1016/j.bbrc.2015.11.128
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发表时间：
2016-04-08
影响因子：
3.1
通讯作者：
Tang, Chao-Ke
中科院分区：
文献类型：
--
作者：
Liu, Dan;Zhang, Min;Tang, Chao-Ke
原理：巨噬细胞中胆固醇的过度积累是泡沫细胞形成和动脉粥样硬化发展的主要因素。研究表明miR-486在心血管疾病中发挥重要作用，但其作用机制尚不清楚。目的：本研究旨在探讨miR-486是否调控ATP结合盒转运蛋白A1（ABCA 1）介导的胆固醇外排，并探讨其作用机制。基于生物信息学分析和荧光素酶报告基因分析，我们将miR-486模拟物和miR-486抑制剂转染THP-1巨噬细胞源性泡沫细胞，发现miR-486直接结合于组蛋白乙酰转移酶-1（HAT 1）3 'UTR，下调其mRNA和蛋白表达。此外，我们通过转染野生型HAT 1和shHAT 1（短发夹HAT 1）的研究发现，HAT 1可以促进ABCA 1在mRNA和蛋白水平的表达。同时，组蛋白H4的赖氨酸5和12的乙酰化水平在用HAT 1过表达后上调。结论：miR-486可通过靶向HAT 1而促进THP-1细胞胆固醇的蓄积。(C)2016 Elsevier Inc. All rights reserved.
Rationale: Excessive cholesterol accumulation in macrophages is a major factor of foam cell formation and development of atherosclerosis. Previous studies suggested that miR-486 plays an important role in cardiovascular diseases, but the underlying mechanism is still unknown.Objective: The purpose of this study is to determine whether miR-486 regulates ATP-binding cassette transporter A1 (ABCA1) mediated cholesterol efflux, and also explore the underlying mechanism.Methods and results: Based on bioinformatics analysis and luciferase reporter assay, we transfected miR-486 mimic and miR-486 inhibitor into THP-1 macrophage-derived foam cells, and found that miR-486 directly bound to histone acetyltransferase-1 (HAT1) 3'UTR, and downregulated its mRNA and protein expression. In addition, our studies through transfection with wildtype HAT1 or shHAT1 (short hairpin HAT1) revealed that HAT1 could promote the expression of ABCA1 at both mRNA and protein levels. At the same time, the acetylation levels of the lysines 5 and 12 of histone H4 were upregulated after overexpression with HAT1. Meanwhile, the results of liquid scintillation counter and high performance liquid chromatography (HPLC) showed that miR-486 promoted cholesterol accumulation in THP-1 macrophages.Conclusion: These data indicated that miR-486 aggravate the cholesterol accumulation in THP-1 cells by targeting HAT1. (C) 2016 Elsevier Inc. All rights reserved.