Lipa regulates myeloid differentiation and is essential for intra-plaque macrophage accumulation during atherosclerosis
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PROVIDER: PRJNA1142942 | ENA |
REPOSITORIES: ENA
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Project description:Lysosomal acid lipase (Lipa), which is primarily produced in the liver, has been identified as one of the earliest and most impactful genetic factors linked to human coronary artery diseases. Despite its original source, it is also found to be highly expressed in macrophages. However, the functional importance of Lipa in macrophages has been largely unknown. Notably, individuals with certain risk alleles demonstrate elevated Lipa expression in monocytes and macrophages, but lower levels of hepatic and plasma Lipa, indicating a potential regulatory role of Lipa on atherosclerosis through its impact on macrophages. The development of atherosclerosis in genetic models lacking Lipa has presented challenges. Our hypothesis is that Lipa deficiency may influence atherosclerosis development by affecting macrophages. In order to investigate this, we established Lipa-deficient mice on an ApoE-knockout background, providing a model that enables us to evaluate the influence of Lipa on atherosclerosis. In our experiments, we observed hepatosplenomegaly and increased myeloid cell differentiation in Lipa−/−ApoE−/− mice fed a high-fat diet, which aligns with observations in humans with LIPA deficiency. Surprisingly, we also discovered that Lipa deficiency led to a significant inhibition of atherosclerosis in both Lipa+/−ApoE−/− and Lipa−/−ApoE−/− mice. Mechanistically, we found that such inhibition was linked to a notable reduction in foam cell formation and macrophage accumulation within atherosclerotic plaques. Notably, reduced Lipa expression in Lipa+/−ApoE−/− mice influenced foam cell formation and macrophage accumulation, but 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.
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