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 som e individuals to resist the development of dietary-induced hypercholes terolemia, thus avoiding attendant cardiovascular atherosclerotic comp lications, has long been the focus of our research. From 1 New Zealand white rabbit that failed to show any cholesterolemic response, we hav e, over the course of 10 years, established a partially inbred strain of strongly cholesterol-resistant rabbits. This achievement has result ed in the production of a large number of cholesterol-resistant animal s for study; more importantly, it has shown that a strong genetic fact or operates in dietary regulation of plasma cholesterol levels. We hav e focused our research on the different possibilities associated with this genetic predisposition. Since the cholesterol-resistant rabbits d o 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 c holesterol 7alpha-hydroxylase and liver bile acid metabolism. We have cloned the complete gene and partial cDNAs for cholesterol 7alpha-hydr oxylase from both normal and cholesterol-resistant rabbits. This has a llowed the discovery of changes in the transcription of this gene in t he cholesterol-resistant rabbits compared with normal littermates. The se cholesterol-resistant rabbits have provided a model demonstrating t hat there are biological means to prevent large dietary loads of chole sterol from accumulating in plasma or tissues. Our hypothesis is that cholesterol-resistant animals increase cholesterol turnover by increas ing bile acid excretion, thus providing a way to reduce plasma cholest erol of either dietary or endogenous origin. The methods and observati ons of our research are presented chronologically in this review.