Lysosomal Acid Lipase: From Cellular Lipid Handler to Immunometabolic Target

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CEs) and triglycerides (TGs) to free cholesterol (FC) and free fatty acids (FFAs), which are then used for metabolic purposes in the cell. The process also occurs in immune cells that adapt their metabolic machinery to cope with the different energetic requirements associated with cell activation, proliferation, and polarization. LAL deficiency (LALD) causes severe lipid accumulation and affects the immunometabolic signature in animal models. In humans, LAL deficiency is associated with a peculiar clinical immune phenotype, secondary hemophagocytic lymphohistiocytosis. These observations suggest that LAL might play an important role in cellular immunometabolic modulation, and availability of an effective enzyme replacement strategy makes LAL an attractive target to rewire the metabolic machinery of immune cells beyond its role in controlling cellular lipid metabolism. LAL is a checkpoint of intracellular lipid homeostasis that controls the amount of FC and FFAs released from the lysosome. LALD is characterized by massive accumulation of esterified cholesterol and triglycerides throughout the body, and in particular, in the liver and macrophages. LAL couples intracellular lipid metabolism to functions of the immune cells by providing FC and FFAs that are used for cell proliferation and acquisition of effector functions. Restoring LAL activity improves metabolic parameters in LALD and ameliorates the immunoinflammatory response. Human recombinant LAL ERT might represent a therapeutic approach to correct impaired immune cell functions.