Hyperlipidemia and atherosclerotic lesion development in LDL receptor-deficient mice fed defined semipurified diets with and without cholate

Past studies of atherosclerosis in mice have used chow-based diets suppleme nted with cholesterol, lipid, and sodium cholate to overcome species resist ance to lesion formation. Similar diets have been routinely used in studies with LDL receptor-deficient (LDLR-/-) mice. The nonphysiological nature an d potential toxicity of cholate-containing diets; have led to speculation t hat atherogenesis in these mice may not accurately reflect the human diseas e process. We have designed a semipurified AIN-76A-based diet that can be f ed in powdered, pelleted, or liquid form and manipulated for the precise ev aluation of diet-genetic interactions in murine atherosclerosis. LDLR-/- mi ce 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 weigh t); 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 choleslerol-supplemented mice compared with controls afte r 6 or 12 weeks of feeding (P<0.01). The total area of oil red O-stained at herosclerotic lesions was determined from digitally scanned photographs. In contrast to the control group, ail mice in cholesterol-supplemented dietar y 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). T he distribution pattern of atherosclerotic lesions was highly reproducible and comparable. The histological features of lesions in mice fed cholate-Er ee or cholate-containing diets were similar, This study shows that sodium c holate is not necessary for the formation of atherosclerosis in LDLR-/- mic e and that precisely defined semipurified diets are a valuable tool for the examination of diet-gene interactions.