Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog

Abstract

Liver membranes from young beagle dogs were found to possess binding sites that resemble the low density lipoprotein (LDL) receptors originally described in cultured human fibroblasts. Treatment of the dogs with colestipol (a bile acid sequestrant) and mevinolin (a cholesterol synthesis inhibitor) produced a 3-fold increase in LDL binding activity. This increase correlated with a 2-fold increase in the fractional catabolic rate for intravenously administered human or canine 125I-labeled LDL, suggesting that the increased hepatic receptors were responsible for the enhanced clearance of LDL from plasma. The hepatic lipoprotein receptors of control and drug-treated dogs resembled human fibroblast LDL receptors in that they bound apoprotein E-containing lipoproteins, such as very low density lipoproteins and a subfraction of high density lipoproteins (HDL1), with 10-fold higher affinity than the apoprotein B-containing lipoprotein LDL; failed to bind canine HDL2 and human HDL3, which are devoid of apoproteins B and E; failed to bind methylated LDL; required calcium; and were destroyed by Pronase. Treatment of dogs with mevinolin not only increased the fractional catabolic rate for LDL but also reduced the synthetic rate for the lipoprotein. The current data suggest that the liver of dogs contains functional LDL receptors that are susceptible to metabolic regulation and that a drug-induced increase in the activity of these receptors can contribute to a lowering of plasma levels of LDL-cholesterol.