Objective— A semisynthetic diet with varying amounts of cholesterol was used to achieve hypercholesterolemia and atherosclerosis in LDL receptor–deficient (LDLR−/−) mice. Atherosclerotic lesions were measured as cross-sectional area at the aortic root and brachiocephalic artery and by en face analysis of aortic lesion area in 209 male and female animals on the C57BL/6J (B6.LDLR−/−) and FVB/NJ (FVB.LDLR−/−) backgrounds.

Methods and Results— The semisynthetic diet containing 4.3% fat and 0.00% or 0.02% cholesterol was sufficient to induce hypercholesterolemia (12.6±2.4 mmol/L) and atherosclerosis in B6.LDLR−/− mice at the aortic root (98 980±37 727 μm²) and brachiocephalic artery (12 039±12 750 μm²) but did not produce significant lesions in the aorta measurable by the en face method. Raising dietary cholesterol to 0.15%, 0.30%, or 0.50% more than doubled plasma cholesterol levels (35.9±8.5 mmol/L) and resulted in significant en face lesions. It also led to a significant increase in atherosclerotic lesion area at the aortic root (547 753±182 151 μm²) and brachiocephalic arteries (125 666±59 339 μm²). Although FVB.LDLR−/− mice developed comparable cholesterol levels, they were relatively atherosclerosis resistant and had many-fold smaller lesions.

Conclusions— These results should aid investigations of atherosclerosis in LDLR−/− mice by informing the selection of diet to be used and the location of lesions to be scored.