Atherosclerosis is a disease of the arterial blood vessels that is often known as hardening of the arteries. It is caused in part by the accumulation in the artery wall of cells (mostly cells known as macrophages) that contain fats (mostly cholesterol).
Understanding how macrophages regulate the amount and type of cholesterol they contain is therefore of importance for understanding the mechanisms underlying atherosclerosis. Daniel Ory and colleagues, at the University of Washington School of Medicine, St. Louis, have now provided new insight into this, showing that the protein NPC1 is a factor protecting mice from atherosclerosis through its function as a regulator of macrophage cholesterol trafficking.
Mice lacking LDLR develop atherosclerosis when fed a high-fat diet, but when the authors manipulated these mice such that their macrophages lacked both LDLR and NPC1 they developed atherosclerosis more rapidly. The accelerated atherosclerosis in the absence of NPC1 was associated with impaired cholesterol efflux from macrophages.
Further analysis revealed that NPC1 was required for the generation of 27-hydroxycholsterol, which binds proteins known as LXRs, and for the LXR-dependent upregulation of proteins involved in cholesterol efflux. These data suggest that variation in NPC1 gene expression might affect how susceptible an individual is to developing atherosclerosis.
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