A. LRP/a2-Macroglobulin Receptor
The lipoprotein receptor-related protein (LRP)/a2-macroglobulin receptor (LRP) has a mass about five times larger than the LDL receptor. It contains many of the same structural domains as the LDL receptor, including a cysteine-rich repeat domain that binds to lipoproteins. In vitro studies have shown that the LRP does not bind to apo-B100, but binds to VLDL particles that have been enriched in apo-E. The binding of LRP to its ligands is dependent upon cell surface proteoglycans. These are proteins containing sulfated carbohydrate residues.
In addition to binding lipoproteins, the LRP also binds to a2-macroglobulin, a plasma protein that binds to proteases and, upon binding, is cleared by the liver. The LRP also binds to plasminogen activators and their inhibitors, such as tissue-type plasminogen activator, urokinase-type plasminogen activator, and their corresponding inhibitors.
TABLE IV Apolipoproteins of the Plasma Lipoproteins
|
A-1, A-2, A-4, B-48, C-1, C-2, C-3, E |
|
|
VLDL |
B-100, C-1, C-2, C-3, E, trace amounts |
|
of A-1, A-2, and A-4 |
|
|
LDL |
90-98% apo B-100 |
|
HDL |
A-1, A-2, sometimes, E |
B. Cubulin
Cubulin is a 460-kDa protein localized to epithelial cells, such as those of the kidney. It plays a role in albumin reabsorption; its absence leads to loss of albumin in the urine. Cubulin also mediates the uptake of the major HDL protein apo-A1 by the kidney.
C. Megalin (gp330)
This receptor is a member of the LDL receptor superfam-ily. It is the antigen that elicits an autoimmune response leading to a disease called Heymann’s glomerulonephritis. It interacts with cubulin and is thought to function together with cubulin in the uptake of apo-A1 by the kidney.
D. A VLDL Receptor (?)
A cDNA encoding another member of the LDL receptor family is expressed in muscle and adipose tissue, but not in liver. It binds to apo-E-containing lipoproteins in vitro, but not to LDL. Based on its tissue localization and binding properties, this protein has been postulated to be a receptor for triglyceride-rich lipoproteins.
E. CD-36
CD-36 is expressed in a variety of tissues, including adipocytes and macrophages. It functions in fatty acid transport and, like scavenger receptors, binds a variety of ligands, including senescent neutrophils, collagen, and malaria-infected erythrocytes.
TABLE III Properties of the Apolipoproteins
|
Apolipoprotein |
Molecular weight (Da) |
Concentration (mg/dl) |
Tissue origin |
Function |
|
Apo-A1 |
28,300 |
90-130 |
Intestine, liver |
LCAT activator |
|
Apo-A2 |
17,000 |
30-50 |
Intestine, liver |
Unknown |
|
Apo-A4 |
46,000 |
10-30 |
Intestine, liver |
Unknown |
|
Apo-B100 |
516,000 |
80-100 |
Liver |
Cholesterol, triglyceride transport, receptor recognition |
|
Apo-B48 |
264,000 |
— |
Intestine |
Triglyceride, cholesterol transport |
|
Apo-C1 |
6,500 |
4-7 |
Liver |
LCAT activator |
|
Apo-C2 |
8,800 |
3-8 |
Liver |
LPL activator |
|
Apo-C3 |
8,750 |
8-15 |
Liver |
LPL inhibitor |
|
Apo-D |
33,000 |
10 |
Liver, intestine, pancreas, kidney, adrenals, brain |
Unknown |
|
Apo-E |
35,000 |
3-6 |
Liver, macrophages, brain, |
Receptor recognition |
|
Adrenal |
||||
|
CETP |
74,000 |
— |
Spleen, liver, small intestine, adrenal |
Cholesterol ester transfer |
|
Lp(a) |
400-700 |
0.4-80 |
Liver, testes, brain |
Unknown |
F. An HDL Receptor, SR-B1
Unlike LDL, HDL can deliver cholesterol to certain tissues (liver and steroidogenic tissues like adrenal, ovary, and leydig cells) without the HDL particle being internalized. The SR-B1 protein mediates the docking of HDL with cells and the delivery of cholesterol ester from the core of the HDL particle to the cells. This receptor is in the scavenger receptor family and is able to bind other lipoproteins in addition to HDL.
The discovery that LDL receptor deficiency in familial hypercholesterolemia is associated with premature atherosclerosis was initially paradoxical. A hallmark of atherosclerotic lesions is the formation of "foam cells"— macrophages and smooth muscle cells that accumulate cytoplasmic cholesterol ester droplets. If these cells lack the LDL receptor, how do they import excessive amounts of cholesterol?
Chemical modification of LDL (e.g., acetylation) abolishes its ability to bind to the LDL receptor. However, the modified LDL binds to other cell surface receptors, termed scavenger receptors. Unlike the LDL receptor, scavenger receptors are not downregulated by cholesterol. Like the LDL receptor, uptake through scavenger receptors leads to accumulation of LDL-derived cholesterol as cytoplasmic cholesterol ester droplets.
Are there any physiological counterparts to in vitro chemical modification of LDL? The polyunsaturated fatty acyl chains of LDL lipids can be oxidized, leading to cleavage and formation of chemically reactive short-chain fatty aldehydes. These aldehydes react with the protein moiety of LDL, apo B-100, converting it to a ligand for scavenger receptors. The discovery of LDL oxidation and its implications for atherosclerosis has ignited a strong interest in the potential role of dietary antioxidants (e.g., vitamins C and E) in the prevention of atherosclersosis.
TABLE V Lipoprotein Receptors
|
Name |
Tissue locations |
|
|
LDL receptor (LDLR) |
LDL, apo-E, hepatitis C virus, Rous sarcoma virus subgroup A, human rhinovirus |
Ubiquitously expressed |
|
LDL receptor-related protein/ «2-macroglobulin receptor (LRP) |
Apo-E, lipoprotein lipase, hepatic lipase, thrombospondin, Pseudomonas exotoxin A, «2-macroglobulin, receptor-associated protein (RAP), lactoferrin, t-PA, u-PA, t-PA:PAI-1, u-PA:PAI-1, elastase-a1-antitrypsin |
Liver, brain, lung, adrenal, intestine, kidney, placenta, ovary, testis |
|
VLDL receptor |
apo-E, Reelin |
Smooth muscle, brain, adipose, adipose, adrenal, testis, ovary, placenta, lung |
|
gp330/megalin (VLDLR) |
LDL, apo-J/clusterin, apolipoproteinH/,6 2-glycoprotein-I, PAI-1, prourokinase, lipopoprotein lipase, aprotinin, transcobalamin-vitamin B12, vitamin D-binding protein, retinol-binding protein, PTH, insulin, ^2-microglobulin, epidermal growth factor, prolactin, lysozyme, cytochrome c, thyroglobulin, plasminogen, albumin, polybasic drugs, RAP, Ca2+ |
Kidney, lung, thyroid, parathyroid, epididymis, ileum, placenta, thymus |
|
Apo-E receptor R2 (apoER2; LR7/8B) |
Apo-E, apo-B100, Reelin, RAP |
Brain, testes, ovary, placenta |
Three scavenger receptors for oxidized LDL have been identified; SR-A1, SR-A2, and CD36 (Table VI). These receptors have also been implicated in the phagocytosis of damaged or apoptotic blood cells (e.g., lymphocytes and erythrocytes). CD36 has been implicated in fatty acid uptake into cells. The scavenger receptors can bind a wide array of molecules other than lipoproteins (e.g., polyan-ions, oligonucleotides, bacterial endotoxin, and crocido-lite asbestos).
