The Protein NPC1 Polices Macrophage Cholesterol Traffic

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.