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| Apolipoprotein B (including Ag(x) antigen) | ||||||||||||||
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| Identifiers | ||||||||||||||
| Symbols | APOB; FLDB | |||||||||||||
| External IDs | OMIM: 107730 MGI: 88052 HomoloGene: 328 | |||||||||||||
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| RNA expression pattern | ||||||||||||||
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| More reference expression data | ||||||||||||||
| Orthologs | ||||||||||||||
| Species | Human | Mouse | ||||||||||||
| Entrez | 338 | 238055 | ||||||||||||
| Ensembl | ENSG00000084674 | ENSMUSG00000020609 | ||||||||||||
| UniProt | P04114 | n/a | ||||||||||||
| RefSeq | NM_000384 (mRNA) | XM_001000646 (mRNA) | ||||||||||||
| NP_000375 (protein) | XP_001000646 (protein) | |||||||||||||
| Location | Chr 2: 21.08 - 21.12 Mb |
Chr 12: 8 - 8.04 Mb |
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| PubMed search | [1] | [2] | ||||||||||||
Apolipoprotein B (APOB) is the primary apolipoprotein of low-density lipoproteins (LDL or "bad cholesterol"), which is responsible for carrying cholesterol to tissues. While it is unclear exactly what functional role APOB plays in LDL, it is the primary apolipoprotein component and is absolutely required for its formation. What is clear is that the APOB on the LDL particle acts as a ligand for LDL receptors in various cells throughout the body (i.e. less formally, APOB "unlocks" the doors to cells and thereby delivers cholesterol to them). Through a mechanism that is not fully understood, high levels of APOB can lead to plaques that cause vascular disease (atherosclerosis), leading to heart disease. There is considerable evidence that levels of APOB are a better indicator of heart disease risk than total cholesterol or LDL. However, primarily for practical reasons, cholesterol, and more specifically, LDL-cholesterol, remains the primary lipid target and risk factor for atherosclerosis.
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Genetic disorders
High levels of APOB are related to heart disease. While there does appear to be a genetic component, the environmental component (what you eat) is a significant factor that should not be ignored.
Hypobetalipoproteinemia is a genetic disorder that can be caused by a mutation in the APOB gene, APOB, although it is usually caused by a mutation in the MTP gene, MTP.
Mouse studies
Most relevant information regarding mouse APOB homologue, mApoB, has come from mouse studies. Mice overexpressing mApoB have increased levels of LDL "bad cholesterol" and decreased levels of HDL "good cholesterol".[1] Mice containing only one functional copy of the mApoB gene show the opposite effect, being resistant to hypercholesterolemia. Mice containing no functional copies of the gene are not viable.[2]
Molecular biology
The protein occurs in the plasma in 2 main isoforms, APOB48 and APOB100. The first is synthesized exclusively by the small intestine, the second by the liver. Both isoforms are coded by APOB and by a single mRNA transcript larger than 16 kb. APOB48 is generated when a stop codon (UAA) at residue 2153 is created by RNA editing. There appears to be a trans-acting tissue-specific splicing gene that determines which isoform is ultimately produced. Alternatively, there is some evidence that a cis-acting element several thousand bp upstream determines which isoform is produced.
As a result of the RNA editing, APOB48 and APOB100 share a common N-terminal sequence, but APOB48 lacks APOB100's C-terminal LDL receptor binding region. In fact, APOB48 is so called because it constitutes 48% of the sequence for APOB100.
APOB 48 is a unique protein to chylomicrons from the small intestine. After most of the lipids in the chylomicron have been digested, APOB48 returns to the liver as part of the chylomicron remnant, where it is endocytosed and degraded.
Role in Innate Immune System
VLDL and LDL lipoproteins interfere with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding Apolipoprotein B, to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.[3]
Role in lipoproteins and atherosclerosis
APOB100 is found in lipoproteins originating from the liver (VLDL, IDL, LDL). Importantly, there is one APOB100 molecule per hepatic-derived lipoprotein. Hence, using that fact, one can quantify the number of lipoprotein particles by noting the total APOB100 concentration in the circulation. Since there is one and only one APOB100 per particle, the number of particles is reflected by the APOB100 concentration. The same technique can be applied to individual lipoprotein classes (e.g. LDL) and thereby enable one to count them as well.
It is well established that APOB100 levels are associated with coronary heart disease, and are even a better predictor of it than is LDL level. A naive way of explaining this observation is to use the idea that APOB100 reflects lipoprotein particle number (independent of their cholesterol content). In this way, one can infer that the number of APOB100-containing lipoprotein particles is a determinant of atherosclerosis and heart disease.
One way to explain the above is to consider that large numbers of lipoprotein particles, and, in particular large numbers of LDL particles, lead to competition at the APOB100 receptor (i.e. LDL receptor) of peripheral cells. Since such a competition will prolong the residence time of LDL particles in the circulation, it may lead to greater opportunity for them to undergo oxidation and/or other chemical modifications. Such modifications may lessen the particles' ability to be cleared by the classic LDL receptor and/or increase their ability to interact with so-called "scavenger" receptors. The net result is shunting of LDL particles to these scavenger receptors. Scavenger receptors typically are found on macrophages, with cholesterol laden macrophages being better known as "foam cells". Foam cells characterize atherosclerotic lesions. In addition to this possible mechanism of foam cell generation, an increase in the levels of chemically modified LDL particles may also lead to an increase in endothelial damage. This occurs as a result of modified-LDL's toxic effect on vascular endothelium as well its ability both to recruit immune effector cells and to promote platelet activation.
Recently, the INTERHEART study found that the ApoB100 / ApoA1 ratio is more effective at predicting heart attack risk, in patients who had had an acute myocardial infarction, than either the ApoB100 or ApoA1 measure alone.[4] In the general population this remains unclear although in a recent study apoB was the strongest risk marker for cardiovascular events.[5]
Interactions
Apolipoprotein B has been shown to interact with PPIB,[6] Calcitonin receptor[6][7] and HSP90B1.[6][7]
See also
References
- ^
Transgenic mice that overexpress mouse apolipoprotein B. Evidence that the DNA sequences controlling intestinal expression of the apolipoprotein B gene are distant from the structural gene. J Biol Chem. 1996 May 17; 271(20): 11963-70; PubMed Free text - ^ Knockout of the Mouse Apolipoprotein B Gene Results in Embryonic Lethality in Homozygotes and Protection Against Diet-Induced Hypercholesterolemia in Heterozygotes. Proc Natl Acad Sci USA. 1995 Feb 28; 92(5): 1774–8; PubMed Full text at PMC: PMC42602
- ^ Peterson MM, Mack JL, Hall PR, Alsup AA, Alexander SM, Sully EK, Sawires YS, Cheung AL, Otto M, Gresham HD. (2008). "Apolipoprotein B is an innate barrier against invasive Staphylococcus aureus infection". Cell Host & Microbe 4 (6): 507–9. PMID 19064256.
- ^ McQueen MJ, Hawken S, Wang X, et al. (July 2008). "Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study". Lancet 372 (9634): 224–33. doi:. PMID 18640459.
- ^ Benn M, Nordestgaard BG, Jensen GB, Tybjaerg-Hansen A (2007). "Improving prediction of ischemic cardiovascular disease in the general population using apolipoprotein B: the Copenhagen City Heart Study.". Arterioscler Thromb Vasc Biol 27 (3): 661–70. PMID 17170368.
- ^ a b c Zhang, Jianying; Herscovitz Haya (Feb. 2003). "Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B". J. Biol. Chem. (United States) 278 (9): 7459–68. doi:. ISSN 0021-9258. PMID 12397072.
- ^ a b Linnik, K M; Herscovitz H (Aug. 1998). "Multiple molecular chaperones interact with apolipoprotein B during its maturation. The network of endoplasmic reticulum-resident chaperones (ERp72, GRP94, calreticulin, and BiP) interacts with apolipoprotein b regardless of its lipidation state". J. Biol. Chem. (UNITED STATES) 273 (33): 21368–73. ISSN 0021-9258. PMID 9694898.
Further reading
- Mahley RW, Innerarity TL, Rall SC, Weisgraber KH (1985). "Plasma lipoproteins: apolipoprotein structure and function.". J. Lipid Res. 25 (12): 1277–94. PMID 6099394.
- Itakura H, Matsumoto A (1995). "[Apolipoprotein B]". Nippon Rinsho 52 (12): 3113–8. PMID 7853698.
- Chumakova OS, Zateĭshchikov DA, Sidorenko BA (2006). "[Apolipoprotein B: structure, function, gene polymorphism, and relation to atherosclerosis]". Kardiologiia 45 (6): 43–55. PMID 16007035.
- Ye J (2007). "Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus.". PLoS Pathog. 3 (8): e108. doi:. PMID 17784784.
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