Resistance to dietary-induced hypercholesterolemia exhibited by a unique strain of New Zealand white rabbits.

The search for a precise metabolic explanation for the capacity of some individuals to resist the development of dietary-induced hypercholesterolemia, thus avoiding attendant cardiovascular atherosclerotic complications, has long been the focus of our research. From 1 New Zealand white rabbit that failed to show any cholesterolemic response, we have, over the course of 10 years, established a partially inbred strain of strongly cholesterol-resistant rabbits. This achievement has resulted in the production of a large number of cholesterol-resistant animals for study; more importantly, it has shown that a strong genetic factor operates in dietary regulation of plasma cholesterol levels. We have focused our research on the different possibilities associated with this genetic predisposition. Since the cholesterol-resistant rabbits do not accumulate cholesterol or its esters in plasma or in any tissue compartments, we investigated several biochemical pathways involved in cholesterol metabolism. We have recently concentrated on the enzyme cholesterol 7 alpha-hydroxylase and liver bile acid metabolism. We have cloned the complete gene and partial cDNAs for cholesterol 7 alpha-hydroxylase from both normal and cholesterol-resistant rabbits. This has allowed the discovery of changes in the transcription of this gene in the cholesterol-resistant rabbits compared with normal littermates. These cholesterol-resistant rabbits have provided a model demonstrating that there are biological means to prevent large dietary loads of cholesterol from accumulating in plasma or tissues. Our hypothesis is that cholesterol-resistant animals increase cholesterol turnover by increasing bile acid excretion, thus providing a way to reduce plasma cholesterol of either dietary or endogenous origin. The methods and observations of our research are presented chronologically in this review.