Lipa regulates myeloid differentiation and is essential for intra-plaque macrophage accumulation during atherogenesis.

Lysosomal acid lipase (LIPA), one of the earliest and most impactful genetic factors linked to human coronary artery diseases, is highly expressed in macrophages despite predominant hepatic production. However, the functional importance of LIPA in macrophages remained largely unknown. Notably, individuals with atherosclerosis-risk alleles demonstrate elevated LIPA expression in monocytes and macrophages, but lower levels in liver and plasma, indicating a potential macrophage-specific regulatory role of LIPA on atherosclerosis. The development of atherosclerosis in genetic models lacking LIPA has presented challenges. To investigate whether macrophage LIPA influences atherosclerosis, we established Lipa-deficient mice on an Apoe-/- background. Lipa-/-Apoe-/- mice developed hepatosplenomegaly and enhanced myelopoiesis after being fed a high-fat diet, which aligns with observations in human Lipa deficiency. Unexpectedly, both Lipa+/-Apoe-/- and Lipa-/-Apoe-/- mice showed significantly attenuated atherosclerosis. This protection was recapitulated in Apoe-/- recipients reconstituted with bone marrow from either Lipa+/-Apoe-/- or Lipa-/-Apoe-/- donors. Mechanistically, such atheroprotection was linked to a notable reduction in foam cell formation and macrophage accumulation within plaques. Homozygous deficiency suppressed foam cells via impaired monocyte development and CD36 downregulation, whereas heterozygosity primarily decreased CD36 expression. In vitro, Lipa-/- macrophages exhibited diminished lipid uptake and CD36 expression, both reversed by Lipa re-expression. Notably, reduced Lipa expression in Lipa+/-Apoe-/- mice did not impact hepatic lipid metabolism or macrophage differentiation, as evidenced by flow cytometry and single-cell RNA sequencing. These findings highlight a novel role for Lipa in modulating macrophage behavior during atherosclerosis, suggesting that Lipa may serve as a promising therapeutic target for the treatment of atherosclerosis.