These findings (1) argue against a direct contribution of macrophages to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility13 and rather (2) suggest that when targeting USF1 in the context of atherosclerotic cardiovascular disease one should actually try to maintain optimal USF1 levels in macrophages to overcome exacerbation of the hypercholesterolemia and macrophage foam cell extent. The gene discussed is USF1; the disease is familial hypercholesterolemia.