The role of the LDL receptor in apolipoprotein B secretion.
Familial hypercholesterolemia is caused by mutations in the LDL receptor gene (Ldlr). Elevated plasma LDL levels result from slower LDL catabolism and a paradoxical lipoprotein overproduction. We explored the relationship between the presence of the LDL receptor and lipoprotein secretion in hepatocytes from both wild-type and LDL receptor-deficient mice. Ldlr(-/-) hepatocytes secreted apoB100 at a 3.5-fold higher rate than did wild-type hepatocytes. ApoB mRNA abundance, initial apoB synthetic rate, and abundance of the microsomal triglyceride transfer protein 97-kDa subunit did not differ between wild-type and Ldlr(-/-) cells. Pulse-chase analysis and multicompartmental modeling revealed that in wild-type hepatocytes, approximately 55% of newly synthesized apoB100 was degraded. However, in Ldlr(-/-) cells, less than 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 lipoprotein particles.
Twisk
J
J
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Gillian-Daniel
D L
DL
Tebon
A
A
Wang
L
L
Barrett
P H
PH
Attie
A D
AD
D000256:Adenoviridae / Q000235:genetics; D000418:Albumins / Q000378:metabolism; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000418:Albumins; D001055:Apolipoproteins B; D002788:Cholesterol Esters; D012333:RNA, Messenger; D011973:Receptors, LDL; D011994:Recombinant Proteins; D014280:Triglycerides; D002784:Cholesterol