The role of the LDL receptor in apolipoprotein B secretion

Familial hypercholesterolemia is caused by mutations in the LDL receptor ge ne (Ldlr). Elevated plasma LDL levels result from slower LDL catabolism and a paradoxical lipoprotein overproduction. We explored the relationship bet ween the presence of the LDL receptor and lipoprotein secretion in hepatocy tes from both wild-type and LDL receptor-deficient mice. Ldlr(-/-) hepatocy tes secreted apoB100 at a 3.5-fold higher rate than did wild-type hepatocyt es. ApoB mRNA abundance, initial apoB synthetic rate, and abundance of the microsomal triglyceride transfer protein 97-kDa subunit did not differ betw een wild-type and Ldlr(-/-) cells. Pulse-chase analysis and multicompartmen tal modeling revealed that in wild-type hepatocytes, approximately 55% of n ewly synthesized apoB100 was degraded. However, in Ldlr(-/-) cells, less th an 20% of apoB was degraded. In wild-type hepatocytes, approximately equal amounts of LDL receptor-dependent apoB100 degradation occured via reuptake and presecretory mechanisms. Adenovirus-mediated overexpression of the LDL receptor in Ldlr(-/-) cells resulted in degradation of approximately 90% of newly synthesized apoB100. These studies show that the LDL receptor alters the proportion of apoB that escapes co- or post-translational presecretory degradation and mediates the reuptake of newly secreted apoB-containing li poprotein particles.