Receptor-mediated endocytosis of LDL:
Two different types of lipoprotein receptors have been identified. The first one present receptors that bind lipoproteins presenting exogenous cholesterol absorbed from the intestine (chylomicron remnant receptors); the other one is responsible for uptake of cholesterol carrying lipoproteins derived from the liver and other nonintestival sources (LDL receptors) (Goldstein and Brown, 1987). Since these receptors are regulated by different genes, they promote different models of metabolic regulation.
Focusing on the LDL receptors:
The main ligand on LDL receptors is ApoB-100 on the LDL molecule; nonetheless this receptor can also be activated by VLDL, IDL and HDL due to existence of multiple copies of ApoE in such lipoproteins (Daniels, 2009). The LDLR is composed by three protein modules: a domaisn with seven contiguous cysteine-rich repeats, a400-amino acid sequence and a 58-residue sequence rich in serine and threonine.
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| Endocytosis |
After the endocytosis, a receptor-ligand complex (called lysosome) is formed, in which all of the components of LDL are absolutely degraded by acid hydrolases. The LDLR peptide is recovered back to the membrane; meantime, the larger portion of lipids (cholesteryl esters) is hydrolysed by lysosomal acid lipase (LIPA) into free cholesterol. This cholesterol may be integrated into the cell membranes or play an important role in efflux to cellular adaptors, conversion back into cholesterol esters, metabolism into bile acids or synthesis of steroids, according to different cell types.
When there is cholesterol overloading, the efflux process, by macrophage foam cells, become extremely important for homeostasis maintenance. One of the possible cholesterol efflux pathways is related to the gene ABCA1. It occurs when the ApoA1 (Apolipoprotein A-1) binds to ABCA1, avoiding its deterioration and expanding the level of ABCA1 transporter in the plasma membrane. The ABCA1 transporter and ApoA-1 interaction promote the movement of free cholesterol across the cell membrane, resulting in the formation of discoidal HDL molecules. The efflux process is known by its importance in preventing atherosclerosis in humans.
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| . Summary of ABCA1 activity in the plasmamembrane of cells and formation of nascent HDL particles. |