Delayed clearance of very low density and intermediate density lipoprotein with enhanced conversion to low density lipoprotein in WHHL rabbits

Rabbit livers express two genetically distinct receptors for plasma lipoproteins: the low density lipoprotein (LDL) receptor and the chylomicron remnant receptor. In homozygous Watanabe-heritable hyperlipidemic (WHHL) rabbits, an animal model for human familial hypercholesterolemia, LDL receptors are genetically deficient, but chylomicron remnant receptors are normal. Hence, WHHL rabbits clear LDL from the circulation at an abnormally slow rate, but they clear chylomicron remnants at a normal rate. The current studies show that WHHL rabbits clear ¹²⁵I-labeled very low density lipoprotein (VLDL) and its metabolic product, intermediate density lipoprotein (IDL), from plasma at a markedly decreased rate. The impaired clearance is due to a profound decrease in the rate of uptake of ¹²⁵I-labeled VLDL and ¹²⁵I-labeled IDL by the liver. Because of its rapid clearance in normal rabbits, only a fraction of the ¹²⁵I-labeled apoprotein B component of VLDL is converted to LDL. In WHHL rabbits, the impaired clearance of VLDL leads to a markedly increased conversion of ¹²⁵I-labeled apoprotein B from VLDL to LDL. These results indicate that: in rabbits, the LDL receptor mediates the rapid removal of VLDL and IDL from plasma, and, a deficiency of LDL receptors leads to an enhanced conversion of VLDL to LDL. The combination of overproduction and impaired plasma clearance of LDL, both resulting from a single gene mutation in the LDL receptor, leads to a massive increase of plasma LDL levels in homozygous WHHL rabbits.