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

• Published in: Molecular therapy 2020-01, Vol.28 (1), p.202-216
• Main Authors: Xu, Yanyong, Xu, Yang, Zhu, Yingdong, Sun, Huihui, Juguilon, Cody, Li, Feng, Fan, Daping, Yin, Liya, Zhang, Yanqiao
• Format: Article
• Language: English
• Subjects: ABCA1; ABCA1 protein; ABCG1; Adipocytes; Animals; Arteriosclerosis; Atherosclerosis; Atherosclerosis - metabolism; ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter 1 - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 1 - metabolism; ATP-binding protein; Binding sites; Cardiovascular disease; Cell Polarity - genetics; Cholesterol; Cholesterol - metabolism; cholesterol efflux; Cytochrome P450; Disease Models, Animal; Gene expression; Hep G2 Cells; Homeostasis; Humans; Hydroxylase; Inflammation; Intestine; Liver; Liver X receptors; Liver X Receptors - metabolism; LXR; Macrophages; Macrophages - metabolism; Male; Metabolic disorders; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-34a; miRNA; Molecular modelling; Original; Pathogenesis; Protein expression; RAW 264.7 Cells; Senescence; THP-1 Cells; Transfection; Tumor necrosis factor-TNF
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.09.008

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. [Display omitted] Atherosclerosis is the leading cause of death in Western countries. Zhang and colleagues show that microRNA-34a (miR-34a) plays a key role in regulating macrophage cholesterol efflux, inflammation, and atherosclerosis. They also show that antagonism of miR-34a promotes regression of atherosclerosis and improves metabolic homeostasis.