SIRT6 reduces macrophage foam cell formation by inducing autophagy and cholesterol efflux under ox‐LDL condition

SIRT 6 is a pivotal regulator of lipid metabolism. It is also closely connected to cardiovascular diseases, which are the main cause of death in diabetic patients. We observed a decrease in the expression of SIRT 6 and key autophagy effectors ( ATG 5, LC 3B, and LAMP 1) in ox‐ LDL ‐induced foam cells, a special form of lipid‐laden macrophages. In these cells, SIRT 6 WT but not SIRT 6 H133Y overexpression markedly reduced foam cell formation, as shown by Oil Red O staining, while inducing autophagy flux, as determined by both mRFP ‐ GFP ‐ LC 3 labeling and transmission electron microscopy. Silencing the key autophagy initiation gene ATG 5 , reversed the autophagy‐promoting effect of SIRT 6 in ox‐ LDL ‐treated THP 1 cells, as evidenced by an increase in foam cells. Cholesterol efflux assays indicated that SIRT 6 overexpression in foam cells promoted cholesterol efflux, increased the levels of ABCA 1 and ABCG 1, and reduced miR‐33 levels. By transfecting miR‐33 into cells overexpressing SIRT 6, we observed that reduced foam cell formation and autophagy flux induction were largely reversed. These data imply that SIRT 6 plays an essential role in protecting against atherosclerosis by reducing foam cell formation through an autophagy‐dependent pathway.