Abstract
In the development of atherosclerotic plaques, macrophages infiltrate the intima of the aortic wall to digest modified lipoproteins. Over time, these macrophages become overloaded with lipids and become plaque-associated foam cells. Most modified lipoproteins are aggregated and cross-linked to the extracellular matrix of the vessel wall, which prevents them from being phagocytosed by macrophages. Our lab has described how macrophages catabolize aggregated LDL extracellularly in a process termed digestive exophagy. Macrophage forms a tightly sealed, acidified extracellular compartment around agLDL that is stabilized by F-actin. Lysosomes are secreted into this extracellular compartment, allowing lysosomal acid lipase to catabolize cholesteryl esters in the core of agLDL to free cholesterol. However, it remains unclear how the extracellular free cholesterol is transported into macrophages for lipid droplet formation. Here, we identify the cholesterol transport protein StarD4 as a major player in the intracellular movement of free cholesterol released by digestive exophagy. We show that StarD4 knockout bone marrow-derived macrophages have delayed onset in foam cell formation when encountering agLDL. However, no difference is observed when StarD4 knockout macrophages are treated with monomeric acetylated LDL, suggesting the effect of StarD4 is specific to cholesterol delivered to the plasma membrane. Moreover, loss of StarD4 does not alter the rate of digestive exophagy, and no difference in lysosome exocytosis is observed between StarD4 knockout and wildtype macrophages. Therefore, our results indicate that StarD4 mediated plasma membrane to ER cholesterol transport is a critical step in digestive exophagy of agLDL. Loss of StarD4 can delay the onset of foam cell formation, which may provide insight into novel therapeutic strategies for atherosclerosis.
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