Abstract
Diets currently used to produce atherosclerotic lesions in mice are often undefined and cause accumulation of fat in the liver and gallstone formation. Therefore, synthetic low and high fat diets of known composition were formulated in this study. A synthetic diet containing 50% sucrose, 15% cocoa butter, 1% cholesterol, and 0.5% sodium cholate was found to produce a depression in high density lipoprotein cholesterol (HDL-C) and an elevation of very low density lipoprotein (VLDL) and low density lipoprotein cholesterol (LDL-C) in the atherosclerosis-susceptible strain, C57BL/6J. This diet was able to consistently produce aortic lesions and led to a decrease in liver damage and gallstone formation. The synthetic low fat diet did not produce HDL-C levels as high as those found in mice fed chow, but resulted in similar VLDL/LDL-C levels. Lipoprotein and apolipoprotein parameters were compared in C57BL/6J and the atherosclerosis-resistant strain, C3H/HeJ, consuming the synthetic low fat or high fat diets. As reported earlier, when consuming a high fat diet C57BL/6J mice have significantly lower HDL-C and apoA-I levels than C3H/HeJ mice. Further analysis shows that the molar ratio of plasma HDL-C to apoA-I is significantly lower in C57BL/6J mice, suggesting that HDL in the susceptible strain has a lower cholesterol-carrying capacity. This conclusion is consistent with the observation that the HDL particle size is smaller for C57BL/6J mice than for C3H/HeJ. Both strains increased their apoE levels when fed the synthetic high fat diet, but C3H/HeJ mice had higher levels of apoE on both diets. The major response to consumption of the high fat diet for both strains was an increase in apoB-48 from 5 micrograms/ml on a low fat diet to 54 and 109 micrograms/ml for C57BL/6J and C3H/HeJ, respectively. ApoB-100 showed minimal response to the high fat diet. The defined high fat diet can be used to study atherosclerosis in the mouse since it produces aortic lesions but reduces or eliminates other pathological changes such as gallstone formation and liver damage.
Highlights
Diets currently used to produce atherosclerotic lesions in mice are often undefined and cause accumulation of fat in the liver and gallstone formation
As a first step in formulating a synthetic high fat diet that would produce atherosclerotic lesions in mice, eight synthetic diets were evaluated to determine which fat and carbohydrate sources produced a plasma lipoprotein profile similar to that produced by the ninth diet, the control atherogenic diet currently used in this laboratory
Previous attempts to produce a synthetic atherogenic diet demonstrated that a reduction in high density lipoprotein cholesterol (HDL-C) and an elevation in very low density lipoprotein (VLDL)/low density lipoprotein (LDL) were both required for the development of aortic lesions in B6 mice
Summary
Diets currently used to produce atherosclerotic lesions in mice are often undefined and cause accumulation of fat in the liver and gallstone formation. A synthetic diet containing 50 % sucrose, 15% cocoa butter, 1% cholesterol, and 0.5% sodium cholate was found to produce a depression in high density lipoprotein cholesterol (HDL-C) and an elevation of very low density lipoprotein (VLDL) and low density lipoprotein cholesterol (LDL-C) in the atherosclerosis-susceptible strain, C57BL/6J This diet was able to consistently produce aortic lesions and led to a decrease in liver damage and gallstone formation. Differences observed in the formation of lipidstaining lesions in the aorta and HDL-cholesterol levels in mice in response to high fat feeding has made it possible to identify two genes, Ath-1 and Ath-2, determining susceptibility or resistance to atherosclerosis [1, 3] Previous studies in this laboratory to identify such genetic factors have relied on the use of nondefined diets [3, 4]. Inbred strains of mice are a useful experimental tool to study the etiology and development of atherosclerosis, They offer a system to characterize genetic variants of lipoproteins [1] and apolipoproteins [2] and to subse-
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