Dataset Information

Fibroblast growth factor 21 potentially inhibits microRNA-33 expression to affect macrophage actions.

ABSTRACT: Atherosclerosis is a chronic inflammatory disease with complex pathological processes. MicroRNA-33 (miR-33), a novel non-coding RNA that coexpresses with sterol regulatory element-binding proteins (SREBPs), affects macrophage actions to prevent atherosclerosis. Fibroblast growth factor 21 (FGF21) is an important regulator of lipid metabolism, especially for macrophage-related cholesterol export, but the mechanism is not fully studied. Interestingly, FGF21 has been evidenced to prevent atherosclerosis via inhibiting SREBP-2 expression. Therefore, we speculate that FGF21 may be a potential regulator for miR-33 with an aim of insight into novel anti-atherosclerotic mechanisms and research fields.

SUBMITTER: Guo Y

PROVIDER: S-EPMC5134291 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fibroblast growth factor 21 potentially inhibits microRNA-33 expression to affect macrophage actions.

Guo Yuan Y Luo Fei F Yi Yuhong Y Xu Danyan D

Lipids in health and disease 20161201 1

Atherosclerosis is a chronic inflammatory disease with complex pathological processes. MicroRNA-33 (miR-33), a novel non-coding RNA that coexpresses with sterol regulatory element-binding proteins (SREBPs), affects macrophage actions to prevent atherosclerosis. Fibroblast growth factor 21 (FGF21) is an important regulator of lipid metabolism, especially for macrophage-related cholesterol export, but the mechanism is not fully studied. Interestingly, FGF21 has been evidenced to prevent atheroscle ...[more]

PMID: 27905947

Similar Datasets

Project description:BackgroundCardiac macrophages (cMPs) are increasingly recognized as important regulators of myocardial homeostasis and disease, yet the role of noncoding RNA in these cells is largely unknown. Small RNA sequencing of the entire miRNomes of the major cardiac cell fractions revealed microRNA-21 (miR-21) as the single highest expressed microRNA in cMPs, both in health and disease (25% and 43% of all microRNA reads, respectively). MiR-21 has been previously reported as a key microRNA driving tissue fibrosis. Here, we aimed to determine the function of macrophage miR-21 on myocardial homeostasis and disease-associated remodeling.MethodsMacrophage-specific ablation of miR-21 in mice driven by Cx3cr1-Cre was used to determine the function of miR-21 in this cell type. As a disease model, mice were subjected to pressure overload for 6 and 28 days. Cardiac function was assessed in vivo by echocardiography, followed by histological analyses and single-cell sequencing. Cocultures of macrophages and cardiac fibroblasts were used to study macrophage-to-fibroblast signaling.ResultsMice with macrophage-specific genetic deletion of miR-21 were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload of the left ventricle. Single-cell sequencing of pressure-overloaded hearts from these mice revealed that miR-21 in macrophages is essential for their polarization toward a M1-like phenotype. Systematic quantification of intercellular communication mediated by ligand-receptor interactions across all cell types revealed that miR-21 primarily determined macrophage-fibroblast communication, promoting the transition from quiescent fibroblasts to myofibroblasts. Polarization of isolated macrophages in vitro toward a proinflammatory (M1-like) phenotype activated myofibroblast transdifferentiation of cardiac fibroblasts in a paracrine manner and was dependent on miR-21 in cMPs.ConclusionsOur data indicate a critical role of cMPs in pressure overload-induced cardiac fibrosis and dysfunction and reveal macrophage miR-21 as a key molecule for the profibrotic role of cMPs.

Project description:OBJECTIVE:Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis. APPROACH AND RESULTS:Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression of autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux upon genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic Ldlr-/- mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis. CONCLUSIONS:Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.

Dataset Information

Fibroblast growth factor 21 potentially inhibits microRNA-33 expression to affect macrophage actions.

Publications

Fibroblast growth factor 21 potentially inhibits microRNA-33 expression to affect macrophage actions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets