BILE-ACID EXCRETION AND CHOLESTEROL 7-ALPHA-HYDROXYLASE EXPRESSION INHYPERCHOLESTEROLEMIA-RESISTANT RABBITS

We have developed a partially inbred substrain of New Zealand white ra bbits (CRT/mlo) that are resistant to the hypercholesterolemia that ac companies cholesterol feeding to normal rabbits. The plasma cholestero l concentration of normal rabbits increases dramatically from about 30 mg/dl to >300 mg/dl after they are fed a 0.1% cholesterol-enriched di et for 3-4 months. Cholesterol-fed CRT/mlo animals, however, maintain a cholesterol level of about 30 mg/dl during the entire cholesterol fe eding period. In addition to the low plasma cholesterol level, measure ments of cellular cholesterol indicate that the hepatic cholesterol co ntent of the cholesterol-fed resistant rabbit remains markedly lower t han it does in normal animals fed the same diet. The only mechanism fo r removal of significant quantities of cholesterol carbon from the bod y is via the fecal excretion of cholesterol, neutral sterol metabolite s, and bile acids. In comparison to the basal, low-cholesterol diet, w e observed that cholesterol-fed resistant rabbits had increased excret ion of lithocholic acid, while excretion of this bile acid by choleste rol-fed normal rabbits remained similar to basal diet levels. Deoxycho lic 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 sign ificantly less in the resistant rabbits. Thus, the resistant rabbits e xcreted relatively more lithocholic and deoxycholic acid than did the cholesterol-fed normal rabbit. The difference in bile acid excretion w as also manifest by a higher than normal level of cholesterol 7alpha-h ydroxylase activity and cholesterol 7alpha-hydroxylase mRNA in the liv ers from resistant versus normal rabbits. As cholesterol 7alpha-hydrox ylase is the putative rate-limiting step of bile acid synthesis, we be lieve that the increased excretion of bile acids by resistant animals is due, at least in part, to increased levels of cholesterol 7alpha-hy droxylase expression.