Abstract 18944: The Mir-33 Locus Coordinately Regulates Macrophage Autophagy
Autophagy, which promotes the degradation of cytoplasmic components in lysosomes, is essential for maintaining cellular homeostasis. Defective autophagy in macrophages of the artery wall leads to a number of pathologic processes, including activation of the inflammasome, defective efferocytosis, and impaired cholesterol metabolism. Autophagy of lipid droplets (LDs) or “lipophagy” catabolizes stored lipids and plays a key role in cholesterol efflux by regulating LD-cholesterol mobilization, a rate-limiting step in macrophage reverse cholesterol transport (RCT). MicroRNA-33 (miR-33) is a well-established post-transcriptional RCT regulator, yet the complete mechanisms by which anti-miR33 exerts its beneficial effects on cholesterol metabolism are not known. Notably, we have recently shown that miR-33 and its sister strand miR-33* cooperate to regulate autophagy by repressing the expression of key effectors (ATG5, ATG12, LC3B, LAMP1) and initiators (AMPK) of this pathway. Inhibition of endogenous miR-33 and miR-33* increases autophagy in macrophages through derepression of these target genes and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, which regulate autophagy and lysosome biogenesis gene programs. Here, we show that silencing of miR-33 and miR-33* enhances autophagy-dependent lipid droplet catabolism and generation of free cholesterol for efflux, upstream of the ABCA1 transporter, and that autophagy is required for anti-miR33/33* promotion of cholesterol efflux and cytoplasmic LD clearance. Furthermore, anti-miR33 treatment of atherosclerotic Ldlr–/– mice enhanced autophagy in plaque macrophages and triggered atherosclerosis regression. Interestingly, we found that miR-33* was expressed in plaque macrophages at comparable levels to those of miR-33, suggesting that miR-33* / combined miR-33/-33* inhibition may constitute a novel / improved therapeutic strategy to promote RCT and atherosclerosis regression. These data describe an important role for miR-33 and miR-33* in the regulation of autophagy upstream of cholesterol efflux and atheroprotection, providing a better understanding of the mechanisms by which the miR-33 locus coordinates cellular metabolism.
Author Disclosures: M. Ouimet: None. H. Ediriweera: None. B. Ramkhelawon: None. R. Singaravelu: None. X. Liao: None. C. Esau: None. J. Pezacki: None. I. Tabas: None. Y. Marcel: None. K. Rayner: None. K. Moore: None.
- © 2016 by American Heart Association, Inc.