Clearance of VLDL from the plasma by the LDLR is mediated by apoE, but chylomicron remnant clearance is more complex.
[beta]-VLDL accumulate in the plasma because apoE2 is defective in LDLR binding (approximately 2% of normal).
By site-directed mutagenesis or analysis of naturally occurring variants in patients with type III hyperlipoproteinemia, we demonstrated that residues 136 (Arg), 140 (His), 142 (Arg), 143 (Lys), 145 (Arg), 146 (Lys), 147 (Arg), and 150 (Arg) mediate the interaction with the LDLR by interacting with negatively charged residues in the LDLR.
upregulates the LDLRs and a reduction in plasma LDL follows.
Homozygous LPL or apoCII deficiency will result in extreme disruption of CM clearance, diminished VLDL production because of reduced hepatic triglyceride delivery from the gut, and increased clearance of LDL by upregulation of LDLRs.
Statins have their major impact in the liver by lowering cholesterol in hepatocytes, which leads to upregulation of the LDLR and increased removal of LDL from the plasma.
In the case of PCSK9, which is located in the LDLR degradation pathway, its gain-of-function mutations induce an autosomal dominant form of familial hyper-cholesterolemia in humans by reducing LDLRs.
LXR agonists suppress the uptake of LDL by decreasing LDLR proteins rather than mRNA.
To further characterize the different classes of sequence variations, we compared subcellular localization of the mutant LDLRs with known markers of cellular compartments.
Class 4 mutant LDLRs have been described to be unable to assemble in clathrin-coated pits (24).
Gain-of-function sequence variants cause a reduction in the LDLR that leads to hypercholesterolemia (13) or to autosomal dominant hypercholesterolemia in cases of severe phenotypic variants (2, 14).
This work has included identification of the amino acid residues important for PCSK9 autocatalytic processing, secretion, and biological activity--information that provides insight into the mechanism by which PCSK9 mediates LDLR degradation.