Low density lipoprotein receptor deficiency in cultured hepatocytes of the WHHL rabbit. Further evidence of two pathways for catabolism of exogenous proteins.
We have studied hepatocytes cultured from Watanabe-heritable hyperlipidemic (WHHL) rabbits, animals that display striking elevation of plasma low density lipoprotein (LDL), spontaneous atherosclerosis, and an absence of LDL receptor activity in cultured fibroblasts. Degradation of LDL by WHHL hepatocytes differed from degradation by normal hepatocytes in several ways: 1) degradation by normal hepatocytes as a function of LDL concentration was curvilinear with a saturable component, while degradation by WHHL hepatocytes was a linear function of concentration; 2) degradation of 125I-labeled LDL by mutant cells was not decreased by excess unlabeled LDL, while degradation by normal cells was; 3) degradation of LDL by normal cells was inhibited by colchicine and chloroquine while degradation by the mutant cells was not; 4) both cell types catabolized LDL at nearly equal rates, but activity of 3-hydroxy-3-methylglutaryl-CoA reductase was suppressed only in the normal cells. These differences are analogous to those previously reported in describing the qualitatively different pathways for receptor-dependent and receptor-independent catabolism of lactosylated and native human LDL in rat hepatocytes. Thus, hepatocytes from WHHL rabbits lack LDL receptor activity. The peripheral and hepatic LDL receptors most likely are products of the same gene or depend for their activity on a single gene product.
D000818:Animals; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011973:Receptors, LDL
D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D002738:Chloroquine; D006903:Hydroxymethylglutaryl CoA Reductases; D003078:Colchicine