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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:878.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Diet-Induced Hypercholesterolemic Murine Model to Study Atherogenesis Without Obesity and Metabolic Syndrome

Karsten Hartvigsen; Christoph J. Binder; Lotte F. Hansen; Apaïs Rafia; Joseph Juliano; Sohvi Hörkkö; Daniel Steinberg; Wulf Palinski; Joseph L. Witztum; Andrew C. Li

From the Department of Medicine (K.H., C.J.B., L.F.H., A.R., J.J., S.H., D.S., W.P., J.L.W.) and Department of Cellular and Molecular Medicine (A.C.L.), University of California, San Diego, La Jolla, Calif.

Correspondence to Karsten Hartvigsen, PhD, or Andrew C. Li, MD, Department of Medicine, 0682, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682. E-mail khartvigsen{at}ucsd.edu or acli@ucsd.edu

Objective— Western-type high-fat/high-cholesterol diets used to induce atherogenesis in low-density lipoprotein (LDL) 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 LDL receptor-deficient mice were fed regular chow (RC; 0.01% cholesterol/4.4% fat), cholesterol-enriched regular chow (HC; 1% cholesterol/4.4% fat), or Western diet (WD 0.06% cholesterol/21% milk fat) for 28 weeks. HC-feeding led to elevated plasma (20.7 mmol/L [800 mg/dL]) and LDL cholesterol and accelerated atherosclerosis. Plasma triglycerides were unaffected. Compared with RC-fed controls, HC-fed mice had normal body weight gain and normal fasting levels of glucose, free fatty acids, and insulin. In contrast, WD-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 HC-fed and WD-fed mice, lesions in aortic origin cross sections were significantly larger in WD-fed mice. However, morphology was similar in lesions of equal size.

Conclusions— The HC 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.

High-fat/high-cholesterol diets commonly used to induce atherogenesis in LDLR^–/– mice also induce the metabolic syndrome. This study demonstrates that cholesterol enrichment of regular chow provides a simple atherogenic diet that moderately elevates LDL cholesterol generating a human-like lipoprotein profile and avoids confounding effects of the metabolic syndrome.

Key Words: atherosclerosis • insulin resistance • lipoproteins • metabolic syndrome • mouse models