Deficient Chaperone-Mediated Autophagy Promotes Lipid Accumulation in Macrophage

Chaperone-mediated autophagy (CMA) serves as a critical upstream regulator of lipophagy and lipid metabolism in hepatocyte. However, the role of CMA in lipid metabolism of macrophage, the typical component of atherosclerotic plaque, remains unclear. In our study, LAMP-2A (a CMA marker) was reduced in macrophages exposed to high dose of oleate, and lipophagy was impaired in advanced atherosclerosis in ApoE (-/-) mice. Primary peritoneal macrophages isolated from macrophage-specific LAMP-2A (L2A)-deficient mice exhibited pronounced intracellular lipid accumulation. Lipid regulatory enzymes, including long-chain-fatty-acid-CoA ligase 1 (ACSL1) and lysosomal acid lipase (LAL), were increased and reduced in L2A-KO macrophage, respectively. There were no differences in other lipid-related proteins, such as SR-A, SR-B (CD36), ABCA1, or PLIN2. In conclusion, deficient CMA promotes lipid accumulation in macrophage probably by regulating enzymes involved in lipid metabolism. CMA may represent a novel therapeutic target to facilitate lipid metabolism and alleviate atherosclerosis progression. Graphical abstract