Patients with familial hypercholesterolemia (FH) have increased LDL levels because they do not clear LDL from the circulation efficiently. In addition to the clearance defect, many FH patients overproduce apoB-containing lipoproteins. Until recently, there has been no direct mechanism for explaining the relationship between loss of the LDL receptor and lipoprotein overproduction. We have identified a novel role for the LDL receptor. We showed that early in the secretory pathway, the presence of the LDL receptor can target newly-synthesized apoB for degradation, thus reducing the amount of apoB that is secreted. In addition to this pathway, we have confirmed work of others showing that the LDL receptor can also participate in reuptake of newly-secreted VLDL particles. We hypothesize that the LDL receptor retains apoB within the secretory pathway to enable its assembly with neutral lipids and phospholipids into a mature lipoprotein particle. With the accretion of the lipids, the particle is released and secreted. The experiments in this proposal will test this hypothesis with mice deficient in triglyceride and cholesterol synthesis as a consequence of a mutation in stearoyI-CoA desaturase. We will also use transgenic mice with various mutations in the apoB molecule to identify the segments of apoB that are critical for the interaction with the receptor within the secretory pathway. Finally, we will study various LDL receptor mutations that affect trafficking of the receptor within the cell. This will enable us to differentiate between an interaction with apoB early in the secretory pathway and an interaction that occurs after apoB secretion leading to re-uptake of the lipoprotein particles.
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