[Frontiers in Bioscience 2, d298-308, June 15, 1997]

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John M. Taylor and Jianglin Fan

Gladstone Institute of Cardiovascular Disease, the Department of Physiology, and the Cardiovascular Research Institute, University of California, San Francisco, CA


The rabbit is a herbivore, and typical laboratory chow diets contain ~15% protein, 40-50% carbohydrate, 2% vegetable fat, and 15-25% fiber. On this type of diet, typical plasma cholesterol concentrations for the New Zealand White rabbit are in the range of ~30-65 mg/dl, with young animals (<3 kg body weight) usually found at the upper portion of this range. High density lipoproteins (HDL), the most abundant lipoprotein class in the normal rabbit (summarized in ref. (12)), transport more than half of the circulating cholesterol in fasting rabbit plasma (6, 13).

Supplementing the diet with cholesterol rapidly results in a marked increase in the production of cholesteryl ester-rich, beta-migrating very low density lipoproteins (beta-VLDL) by the liver and intestine. The VLDL become the major class of plasma lipoproteins (14-16). Subsequent clearance of the beta-VLDL by the liver is reduced due to a downregulation of cell-surface lipoprotein receptors and the saturation of the remaining receptors (17). Two additional factors exacerbate the response of the rabbit: the relatively efficient absorption of dietary cholesterol and limited hepatic conversion of cholesterol to bile acids (18-20). The beta-VLDL, including chylomicron remnants, that accumulate in the circulation are highly atherogenic. Plasma levels correlate closely with the extent of lesion development (21).

Hypercholesterolemia in the rabbit also can be induced by feeding diets that are high in animal protein (summarized in ref. (22)). In response to a casein-supplemented diet, there is a greater reabsorption of bile acids by the small intestine into circulation that leads to an increased uptake by the liver. The consequence is an inhibition in the conversion of cholesterol to bile acids by the liver due to dramatically decreased levels of mRNA encoding 7-alpha-hydroxylase, which catalyzes the rate-limiting step in bile acid synthesis (23). The resultant elevation in liver cholesterol content leads to an increase in VLDL production, a decrease in lipoprotein receptor activity, and an accumulation of cholesteryl ester-rich VLDL and LDL in the plasma. This change in plasma lipoproteins leads to the development of advanced atherosclerotic lesions (6).

Important genetic variants of the New Zealand White rabbit have been identified that confirm the link between plasma cholesterol and atherosclerosis. An important model for human familial hypercholesterolemia, the Watanabe heritable hyperlipidemic (WHHL) rabbit, has defective LDL receptors. Thus, LDL accumulate in plasma to high levels (24), with homozygotes having plasma cholesterol levels in excess of 400 mg/dl (25). The WHHL rabbit develops complex fibrous lesions that are rich in foam cells (26). The St. Thomas Hospital strain of hyperlipidemic rabbits has increased levels of VLDL, intermediate density lipoproteins (IDL), and LDL due to an apparent overproduction of these lipoproteins, making this variant a potential model for familial combined hyperlipidemia (27). In these rabbits, the strongest predictor of aortic atherosclerosis is an elevated level of IDL.

At the opposite end of the spectrum, a partially inbred line of cholesterol-resistant rabbits has been established that does not readily develop atherosclerosis (28). When they are fed a cholesterol-supplemented diet, the levels of total plasma cholesterol, VLDL, and LDL remain essentially unchanged. These effects may be the result of an enhanced production and secretion of bile salts due to elevated levels of 7-alpha-hydroxylase mRNA (29). However, the findings that both fibroblasts and hepatocytes from the resistant animals have increased rates of cholesterol synthesis, decreased rates of cholesterol esterification, and an increased uptake of LDL indicate that the basis for cholesterol resistance may be more complex (30).