RESUMO
BACKGROUND AND AIMS: Atherosclerosis (AS) is the leading cause of cardiovascular diseases. PGC-1α is a key regulator of cellular energy homeostasis, but its role in AS remains debatable. METHODS AND RESULTS: In our study, PGC-1α was shown to be significantly decreased in the media of human atherosclerotic vessels. To explore whether miRNAs might be regulated by PGC-1α in vascular smooth muscle cells (VSMCs), microarray analysis was performed. Microarray and Pearson's correlation analysis showed that PGC-1α and miR-378a were positively correlated in vivo and in vitro. As an upstream co-activator, PGC-1α was found to regulate miR-378a through binding to the transcriptional factor NRF1 in VSMCs. Therefore, the decreased expression of PGC-1α might account for suppression of miR-378a in VSMCs in AS. Furthermore, IGF1 and TLR8, two genes known to be aberrantly up-regulated in atherogenic vessels, were identified as direct targets of miR-378a. In vitro up-regulation of miR-378a markedly inhibited free fatty acid (FFA)-induced VSMC proliferation, migration and inflammation through targeting IGF1 and TLR8. CONCLUSIONS: These findings highlight the protective role of the PGC-1α/NRF1/miR-378a regulatory axis in AS progression and suggest miR-378a as potential therapeutic target for AS treatment.
Assuntos
Aterosclerose/metabolismo , Movimento Celular , Proliferação de Células , Inflamação/metabolismo , MicroRNAs/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/patologia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , MicroRNAs/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fator 1 Nuclear Respiratório/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Transdução de Sinais , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/metabolismoRESUMO
The global rise in obesity has become a public health crisis. During the onset of obesity, disrupted catecholamine signals have been described to contribute to excess fat accumulation, however, the molecular and metabolic change of subcutaneous adipose tissue (SAT) upon chronic high-fat feeding has rarely been investigated. Here, we show that chronic high-fat feeding caused a significant decrease in the expression of thermogenic genes and acquisition of partial deleterious features of visceral fat in SAT. Upregulated miR-149-3p was involved in this obesity-induced "visceralization" of SAT via inhibiting PRDM16, a master regulator that promoted SAT thermogenesis. Reduction of miR-149-3p significantly increased PRDM16 expression in SAT, with improved whole-body insulin sensitivity, decreased SAT inflammation, and liver steatosis in high-fat fed mice. These findings provided direct evidence of the anti-obese and anti-diabetic effect of PRDM16 in the obese background for the first time and identified that miR-149-3p could serve as a therapeutic target to protect against diet-induced obesity and metabolic dysfunctions.