Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia

The WHHL (Watanabe heritable hyperlipidemic) rabbit has been proposed as an animal model for human familial hypercholesterolemia. Homozygous WHHL rabbits have marked increases in the plasma levels of low density lipoprotein (LDL), removal of LDL from their plasma is delayed, and LDL receptors are absent from their cultured fibroblasts [Tanzawa, K., Shimada, Y., Kuroda, M., Tsujita, Y., Arai, M. & Watanabe, Y. (1980) FEBS Lett. 118, 81-84]. We here report that membranes from the liver and adrenal gland of WHHL rabbits lack high-affinity LDL receptors. In normal rabbit membranes, binding of LDL to this receptor requires calcium and is inhibited by EDTA. The LDL receptor binds rabbit ¹²⁵I-labeled β-migrating very low density lipoprotein (β-VLDL), which contains apoproteins B and E, as well as rabbit ¹²⁵I-labeled LDL, which contains only apoprotein B. It does not bind high density lipoprotein or methyl-LDL. All of these properties are identical with those of the LDL receptor of cultured fibroblasts. We conclude that a deficiency of hepatic and adrenal LDL receptors contributes to the hypercholesterolemia of the WHHL rabbits.