The anti-atherosclerosis effect and molecular mechanism of AMPKα1 by polarizing monocytes to an M2 phenotype via cell-intrinsic lysosomal lipolysis

Regulating the differentiation of monocytes into M2 macrophages can promote the regression of Atherosclerosis (AS) plaque. However, the key molecules regulating the differentiation of monocytes to M2 are unknown. In this study, we reported that adenosine-activated protein kinase α1 (AMPKα1) plays an anti-AS role by polarizing monocytes to an M2 phenotype via promoting fatty acid oxidation (FAO). AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to provide fatty acids for FAO. Furthermore, AMPKα1 can induce lysosomal biogenesis and enhance lipolysis by promoting the transcription factor EB (TFEB) expression and facilitating TFEB nuclear translocation. In conclusion, AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to produce fatty acids, which may represent a mechanism to promote FAO and inflammatory monocytes differentiation towards M2 phenotype.