Macrophage mitochondrial energy status regulates cholesterol efflux and is enhanced by anti‐miR33 in atherosclerosis

Abstract

Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis and miR‐33 has emerged as novel regulator of cholesterol homeostasis. Cellular energy status can significantly influence macrophage function, and bioinformatic analysis predicts that miR‐33 represses a cluster of genes controlling energy metabolism that may contribute to macrophage cholesterol efflux. We hypothesize that miR‐33 represses mitochondria metabolic pathways to reduce cholesterol efflux. Here, we show that macrophage cholesterol efflux is regulated by mitochondrial ATP production and that miR‐33 controls a network of genes that synchronize mitochondrial function. Macrophage cholesterol efflux capacity was markedly reduced by ATP synthase inhibition, confirming the importance of mitochondria in the efflux of excess cholesterol. Specifically, anti‐miR33 derepressed the novel target genes PGC‐1α, PDK4 and SLC25A25 and boosted mitochondrial respiration and ATP production, and mitochondrial respiration was key to the pro‐efflux effects of anti‐miR33. Anti‐miR33 therapy in atherosclerotic Apoe‐/‐ mice reduced aortic sinus lesion area, despite no changes in HDL‐C. Also, this therapy increased expression of mitochondrial target genes in vivo, suggesting that the regulation of mitochondrial genetic networks occur in atherosclerotic lesions.ConclusionWe showed that anti‐miR33 therapy de‐represses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, promotes macrophage cholesterol efflux and reduces atherosclerosis.