Intracellular LDL receptor metabolism and classes of mutation

Five principal classes of LDL receptormutations
can be distinguished: (1) receptor null mutations
(R!) due to lack of receptor protein synthesis
in the endoplasmic reticulum (ER); (2) defective
intracellular transport to the Golgi apparatus;
(3) defective extracellular ligand binding;
(4) defective endocytosis (R+ mutations);
and (5) failure to release the LDL molecules inside
the endosome (recycling-defective mutations).
The receptor–LDL complex enters the
cell by endocytosis. In the endosome the LDL including
of apoB-100 is separated from the receptor.
In the lysosome the LDL is broken down
into amino acids and cholesterol. Free
cholesterol activates the enzyme acetyl-CoA
cholesterol transferase (ACAT), which catalyzes
the esterification. The LDL receptor is recycled
to the cell surface in a recycling vesicle. The key
enzyme for endogenous cholesterol synthesis is
3-hydroxy-3-methylglutaryl-CoA reductase
(HMG-CoA reductase). This enzyme is
downregulated by exogenous LDL uptake. LDL
receptor mutations interrupt this control feedback
mechanism and result in increased endogenous
cholesterol synthesis. HMG-CoA reductase
also downregulates LDL receptor protein
synthesis to prevent overloading with
cholesterol.