Macrophage miR-34a Is a Key Regulator of Cholesterol Efflux and Atherosclerosis.

Abstract

Macrophages play a crucial role in the pathogenesis of atherosclerosis, but the molecular mechanisms remain poorly understood. Here we show that microRNA-34a (miR-34a) is a key regulator of macrophage cholesterol efflux and reverse cholesterol transport by modulating ATP-binding cassette transporters ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1). miR-34a also regulates M1 and M2 macrophage polarization via liver X receptor α. Furthermore, global loss of miR-34a reduces intestinal cholesterol or fat absorption by inhibiting cytochrome P450 enzymes CYP7A1 and sterol 12α-hydroxylase (CYP8B1). Consistent with these findings, macrophage-selective or global ablation of miR-34a markedly inhibits the development of atherosclerosis. Finally, therapeutic inhibition of miR-34a promotes atherosclerosis regression and reverses diet-induced metabolic disorders. Our studies outline a central role of miR-34a in regulating macrophage cholesterol efflux, inflammation, and atherosclerosis, suggesting that miR-34a is a promising target for treatment of cardiometabolic diseases.

• Authors: Yanyong Xu, Yang Xu, Yingdong Zhu, Huihui Sun, Cody Juguilon, Feng Li, Daping Fan, Liya Yin, Yanqiao Zhang
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 28 Issue 1 Pg. 202-216 (01 08 2020) ISSN: 1525-0024 [Electronic] United States
• PMID: 31604677 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• ABCA1 protein, human
• ABCA1 protein, mouse
• ABCG1 protein, human
• ABCG1 protein, mouse
• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• Liver X Receptors
• MIRN34 microRNA, human
• MIRN34a microRNA, mouse
• MicroRNAs
• NR1H3 protein, human
• Nr1h3 protein, mouse
• Cholesterol

Topics

• ATP Binding Cassette Transporter 1 (genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 1 (genetics, metabolism)
• Animals
• Atherosclerosis (metabolism)
• Cell Polarity (genetics)
• Cholesterol (metabolism)
• Disease Models, Animal
• Hep G2 Cells
• Humans
• Liver X Receptors (metabolism)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout, ApoE
• MicroRNAs (genetics, metabolism)
• RAW 264.7 Cells
• THP-1 Cells
• Transfection