We have developed a partially inbred substrain of New Zealand white rabbits (CRT/mlo) that are resistant to the
hypercholesterolemia that accompanies
cholesterol feeding to normal rabbits. The plasma
cholesterol concentration of normal rabbits increases dramatically from about 30 mg/dl to > 300 mg/dl after they are fed a 0.1%
cholesterol-enriched diet for 3-4 months.
Cholesterol-fed CRT/mlo animals, however, maintain a
cholesterol level of about 30 mg/dl during the entire
cholesterol feeding period. In addition to the low plasma
cholesterol level, measurements of cellular
cholesterol indicate that the hepatic
cholesterol content of the
cholesterol-fed resistant rabbit remains markedly lower than it does in normal animals fed the same diet. The only mechanism for removal of significant quantities of
cholesterol carbon from the body is via the fecal excretion of
cholesterol, neutral
sterol metabolites, and
bile acids. In comparison to the basal, low-
cholesterol diet, we observed that
cholesterol-fed resistant rabbits had increased excretion of
lithocholic acid, while excretion of this
bile acid by
cholesterol-fed normal rabbit remained similar to basal diet levels.
Deoxycholic acid excretion, the other main
bile acid excreted in the feces of rabbits, was decreased in response to
cholesterol challenge in animals with either resistant or normal phenotypes, but the decrease was significantly less in the resistant rabbits. Thus, the resistant rabbits excreted relatively more lithocholic and
deoxycholic acid than did the
cholesterol-fed normal rabbit. The difference in
bile acid excretion was also manifest by a higher than normal level of
cholesterol 7 alpha-hydroxylase activity and
cholesterol 7 alpha-hydroxylase mRNA in the livers from resistant versus normal rabbits. As
cholesterol 7 alpha-hydroxylase is the putative rate-limiting step of
bile acid synthesis, we believe that the increased excretion of
bile acids by resistant animals is due, at least in part, to increased levels of
cholesterol 7 alpha-hydroxylase expression.