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The role of the LDL receptor in apolipoprotein B secretion
Jaap Twisk, … , P. Hugh R. Barrett, Alan D. Attie
Jaap Twisk, … , P. Hugh R. Barrett, Alan D. Attie
Published February 15, 2000
Citation Information: J Clin Invest. 2000;105(4):521-532. https://doi.org/10.1172/JCI8623.
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Category: Article

The role of the LDL receptor in apolipoprotein B secretion

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Abstract

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.

Authors

Jaap Twisk, Donald L. Gillian-Daniel, Angie Tebon, Lin Wang, P. Hugh R. Barrett, Alan D. Attie

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Figure 6

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Determination of intracellular apoB and albumin levels after adenovirus-...
Determination of intracellular apoB and albumin levels after adenovirus-mediated overexpression of the LDL receptor. Adenovirus infection was as described in the legend to Figure 5. Ldlr–/– hepatocytes were radiolabeled for 7.5 minutes with [35S]methionine/cysteine in the presence of heparin (6 mg/mL), washed once, and chased for the indicated times. Chase times are relative to the addition of radiolabel. Results are the mean of duplicate samples from a single hepatocyte isolation and are representative of results obtained with wild-type cells. Error bars represent the variance between duplicate samples; error bars that are not visible are smaller than the symbol. Open circle, intracellular; filled circle, intracellular + Ad LDLR. There was no detectable apoB secretion by 22.5 minutes.
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