Objective--Western-type high-fat/high-cholesterol diets used to induce atherogenesis in low-density lipoprotein receptor-deficient mice also lead to obesity with concomitant metabolic complications, eg, hypertriglyceridemia, hyperinsulinemia, and insulin resistance. Our aim was to design a diet inducing atherosclerosis through moderate hypercholesterolemia without associated parameters of the metabolic syndrome.

Methods and Results--Male low-density lipoprotein receptor-deficient mice were fed regular chow (0.01% cholesterol/4.4% fat), cholesterol-enriched regular chow (cholesterol-enriched regular chow; 1% cholesterol/4.4% fat), or Western diet (0.06% cholesterol/21% milk fat) for 28 weeks. Cholesterol-enriched regular chow-feeding led to elevated plasma (20.7 mmol/L (800 mg/dL) and low-density lipoprotein cholesterol and accelerated atherosclerosis. Plasma triglycerides were unaffected. Compared with regular chow-fed controls, cholesterol-enriched regular chow-fed mice had normal body weight gain and normal fasting levels of glucose, free fatty acids, and insulin. In contrast, Western diet-fed mice were extremely hypercholesterolemic (>41.4 mmol/L), obese, hypertriglyceridemic, hyperinsulinemic, insulin resistant, and showed adverse health such as skin/fur abnormalities and hepatic steatosis. Although atherosclerotic surface areas in the entire aorta were similar in cholesterol-enriched regular chow-fed and Western diet-fed mice, lesions in aortic origin cross sections were significantly larger in Western diet-fed mice. However, morphology was similar in lesions of equal size.

Conclusions--The cholesterol-enriched regular chow diet induced moderate hypercholesterolemia and extensive atherosclerosis and should be useful to study specific aspects of atherogenesis in the absence of confounding effects of the metabolic syndrome.