Watanabe heritable hyperlipidemic rabbit. Animal model for familial hypercholesterolemia

The Watanabe heritable hyperlipidemic (WHHL) rabbit has proved to be an invaluable animal model of human familial hypercholesterolemia. The mutant low density lipoprotein (LDL) receptor in the WHHL rabbit lacks four amino acids in the third repeat unit of the receptor-binding domain. By the criterion of LDL binding, the WHHL rabbit is receptor-negative; although the receptor is synthesized, it is very slowly glycosylated, and little may reach the cell surface. WHHL rabbits develop fatty intimal streaks and later complicated atherosclerotic lesions, as do cholesterol-fed rabbits. The lipoproteins accumulating in their blood include not only LDL but also remnants of very low density lipoproteins (VLDL). Chylomicron metabolism, however, appears to be normal. Metabolic studies have shown that VLDL are synthesized and secreted by the liver at normal rates, and no particles containing apolipoprotein B-100 are secreted in lipoproteins of higher density. VLDL remnants are metabolized sluggishly, and a much larger fraction than normal is converted to LDL, which, therefore, accumulate not only because of impaired removal, but also as a result of increased formation from VLDL precursors. Both metabolic studies and the responsiveness of WHHL rabbits to dietary perturbations and drugs that affect the number of LDL receptors on hepatocytes suggest that the LDL receptor on cell surfaces in WHHL rabbits recognizes some VLDL remnants, but not LDL. These receptors may also participate in the metabolism of chylomicron remnants.