Antagonism of let-7c reduces atherosclerosis and macrophage lipid accumulation by promoting PGC-1α/LXRα/ABCA1/G1 pathway

Changes in circulating let-7c were significantly associated with the alter in lipid profile, but its role in intracellular lipid metabolism remains unknown. This work was conducted to explore the effects of let-7c on the lipid accumulation in macrophages and uncover the underlying mechanism. Our results showed that let-7c inhibition relieved atherosclerosis progression in apoE-/- mice. In ox-LDL-treatment macrophages, let-7c knockdown suppressed lipid accumulation but does no affect cholesterol intake. Consistent with this, overexpression of let-7c promoted lipid accumulation by reducing the expression of LXR alpha and ABCA1/G1. Mechanistically, let-7c targeted PGC-1 alpha to repress the expression of LXR alpha and ABCA1/G1, thereby regulating cholesterol homeostasis in macrophages. Taken together, these findings suggest that antagonism of let-7c reduces atherosclerosis and macrophage lipid accumulation through the PGC-1 alpha/LXR alpha/ABCA1/G1 axis.