Since LDL particles primarily represent the transport form of cholesterol, their controlled uptake by the cells is essential. This occurs through an ApoBioo-and ApoE-specific receptor (A). The interaction between ligand and receptor is based on their different charges: on the ligand side, the apoproteins provide the alkaline amino acids lysine and arginine (positive charge), while the active center of the receptor contains the acidic amino acids glutamic and aspartic acid (negative charge). The car-boxy terminal end of the receptor reaches through the plasma membrane. On the inside of the membrane, the protein clathrin causes the membrane to cave in and form vesicles that cinch off.
After LDL binds to the receptor, the entire LDL-receptor-complex is endo-cytosed into the cell (B). Lysosomes digest the LDL particles into fatty acids, amino acids, and nonesterified cholesterol. The receptor, as well as the clath-rin involved, can be reused.
The uptake of LDL particles elevates intracellular free cholesterol concentration, triggering a cascade of further events:
These mechanisms control the concentration of unesterified cholesterol in cells. In the liver, endocrine glands, lungs and kidneys, ~90 % of the LDL are taken up via these receptor-mediated activities.
However, in the small intestine and possibly the spleen, a receptor-independent pathway has been shown to exist. Here, the LDL's binding to the cell surface triggers absorptive endocytosis. Apparently, however, this uptake neither inhibits HMG-CoA-reductase nor does it stimulate ACAT.
An additional possibility of LDL uptake exists through the scavenger or acetyl-LDL receptor. This receptor has been shown to exist in macrophages, smooth muscle cells, and endothelial cells. It seems to be responsible primarily for the uptake of lipoproteins modified by oxidative processes (e. g., lipid peroxidation).
This receptor ensures cholesterol supply to the cells even in case of hereditary LDL receptor deficiency (familial hypercholesterolemia). This receptor cannot be down-regulated, so that cholesterol-loaded LDL may accumulate in the cells. This is considered to be a first step towards atherosclerosis.
LDL-receptor synthesis n
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