New mutant rabbit strain with hypercholesterolemia and atherosclerotic lesions produced by serial inbreeding

We have investigated the characteristics of the Kurosawa and Kusanagi hypercholesterolemic (KHC) rabbit, a strain manifesting inherited and persistent hypercholesterolemia and produced by inbreeding from mutants discovered in 1985. These KHC rabbits had abnormally high serum cholesterol, triglyceride, and phospholipid concentrations 8 to 10 times greater than the concentrations in clinically normal Japanese white rabbits (Oryctolagus cuniculus). The KHC rabbits also had decreased serum high-density lipoprotein cholesterol concentration, about one-third the value in clinically normal rabbits. In addition, the serum lipoprotein electrophoretic patterns were characterized by a strong, broad beta-lipoprotein band and a diminished alpha-lipoprotein band. Fractionation of lipoprotein lipids revealed increased cholesterol, phospholipid, and triglyceride in the low-density lipoprotein fraction; increased cholesterol and phospholipid in the very low-density lipoprotein fraction; and decreased cholesterol and triglyceride in the high-density lipoprotein fraction. On the basis of incidence of hypercholesterolemia in mating experiments, this abnormality is thought to have been inherited as a single autosomal recessive gene mutation, and analysis of the low-density lipoprotein receptor indicated that the KHC rabbit has a 12-base pair deletion in the low-density lipoprotein receptor mRNA. Macroscopic analysis of the aorta revealed the atheromatous lesions at 2 months of age, drastically increased lesional areas in the total aortic surface at 8 months of age, and a high incidence of coronary atheromas and xanthomas. Light microscopy revealed two typical lesions in the aorta fatty plaque and medical calcification.(ABSTRACT TRUNCATED AT 250 WORDS)