Hepatic uptake chylomicron remnants in WHHL rabbits: A mechanism genetically distinct from the low density lipoprotein receptor

Homozygous Watanabe hereditary hyperlipidemic (WHHL) rabbits have a near-complete deficiency of low density lipoprotein (LDL) receptors in liver and other tissues. As a result, these rabbits clear LDL from plasma at an abmormally slow rate. In the current studies we show that WHHL rabbits clear chylomicrons from plasma at a normal rate. Chylomicrons are cleared by a two-step process: hydrolysis of triglycerides in extrahepatic tissues to yield cholesteryl ester-rich remnant particles and rapid uptake of the remnant particles and rapid uptake of the remnants by the liver. Normal and WHHL rabbits were given intravenous injections of rat chylomicrons labeled either in the lipid portion with [³H]cholesterol and [¹⁴C]palmitate or in the protein protion with [¹²⁵I]iodine. All radiolabeled components were removed from plasma at comparable rates in normal and WHHL rabbits. Comparable amounts of radioactivity accumulated in livers of animals from both genotypes. In vitro assays showed that liver membranes from WHHL rabbits were markedly deficient in the binding of ¹²⁵I-labeled chylomicron remnants as well as ¹²⁵I-labeled LDL, implying that chylomicron remnants can bind to the hepatic LDL receptor. We conclude that the rabbit liver normally has at least two genetically distinct lipoprotein uptake mechanisms, both of which recognize chylomicron remnants: the LDL receptor and a specific chylomicron remnant uptake mechanism that is not measured adequately by current in vitro membrane binding assays. WHHL rabbits possess a normal chylomicron remnant uptake mechanism that allows them to clear chylomicrons from plasma at a rapid rate despite their genetic deficiency of LDL receptors.