© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Hyperlipidemia and Atherosclerotic Lesion Development in LDL Receptor–Deficient Mice Fed Defined Semipurified Diets With and Without Cholate
From the Vascular Research Division (A.H.L.), Department of Pathology, and the Vascular Medicine and Atherosclerosis Unit (P.L.), Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; the Arthur G. James Cancer Hospital and Research Institute (S.K.C.), Ohio State University, Columbus, Ohio; and the Department of Laboratory Medicine and Pathobiology (K.I., M.I.C.), University of Toronto, Toronto Hospital Research Centre, and the Departments of Laboratory Medicine and Pathobiology, Medicine, and Biochemistry (P.W.C.), University of Toronto, St Michael's Hospital, Toronto, Ontario, Canada.
Correspondence to Andrew H. Lichtman, MD, PhD, Department of Pathology, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115. E-mail alichtman{at}rics.bwh.harvard.edu
Abstract—Past studies of atherosclerosis in mice have used chow-based diets supplemented with cholesterol, lipid, and sodium cholate to overcome species resistance to lesion formation. Similar diets have been routinely used in studies with LDL receptor–deficient (LDLR-/-) mice. The nonphysiological nature and potential toxicity of cholate-containing diets have led to speculation that atherogenesis in these mice may not accurately reflect the human disease process. We have designed a semipurified AIN-76A–based diet that can be fed in powdered, pelleted, or liquid form and manipulated for the precise evaluation of diet–genetic interactions in murine atherosclerosis. LDLR-/- mice were randomly assigned among 4 diets (n=6/diet) as follows: 1, control, 10% kcal lipid; 2, high fat (40% kcal), moderate cholesterol (0.5% by weight); 3, high fat, high cholesterol (1.25% by weight); and 4, high fat, high cholesterol, and 0.5% (wt/wt) sodium cholate. Fasting serum cholesterol was increased in all cholesterol-supplemented mice compared with controls after 6 or 12 weeks of feeding (P<0.01). The total area of oil red O–stained atherosclerotic lesions was determined from digitally scanned photographs. In contrast to the control group, all mice in cholesterol-supplemented dietary groups 2 to 4 had lesions involving 7.01% to 12.79% area of the thoracic and abdominal aorta at 12 weeks (P<0.002, for each group versus control). The distribution pattern of atherosclerotic lesions was highly reproducible and comparable. The histological features of lesions in mice fed cholate-free or cholate-containing diets were similar. This study shows that sodium cholate is not necessary for the formation of atherosclerosis in LDLR-/- mice and that precisely defined semipurified diets are a valuable tool for the examination of diet–gene interactions.
Key Words: atherosclerosis • LDL receptor • dietary lipids • cholesterol • mice
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