MiR-486 regulates cholesterol efflux by targeting HAT1

• Published in: Biochemical and biophysical research communications Vol. 472; no. 3; pp. 418 - 424
• Main Authors: Liu, Dan, Zhang, Min, Xie, Wei, Lan, Gang, Cheng, Hai-Peng, Gong, Duo, Huang, Chong, Lv, Yun-Cheng, Yao, Feng, Tan, Yu-Lin, Li, Liang, Zheng, Xi-Long, Tang, Chao-Ke
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.04.2016
• Subjects: 3' untranslated regions; ABC transporters; acetylation; Atherosclerosis; ATP Binding Cassette Transporter 1 - metabolism; ATP-binding cassette transporter A1; bioinformatics; Cell Line; cholesterol; Cholesterol - secretion; Cholesterol efflux; Down-Regulation - physiology; foam cells; gene expression regulation; high performance liquid chromatography; Histone acetyltransferase 1; Histone Acetyltransferases - metabolism; histones; Humans; luciferase; Macrophages - metabolism; MicroRNAs - metabolism; miR-486; protein synthesis; transfection; Histone acetyltransferase 1; ATP-binding cassette transporter A1; miR-486; Atherosclerosis; Cholesterol efflux
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.11.128

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. 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. 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. These data indicated that miR-486 aggravate the cholesterol accumulation in THP-1 cells by targeting HAT1. •miR-486 is highly conserved during evolution and directly targets the 3′UTR of HAT1 to control its expression.•miR-486 downregulates the acetylation levels of core histones by HAT1, and subsequently inhibits the expression of ABCA1.•miR-486 inhibits cholesterol efflux in THP-1 macrophages.