• artery morphogenesis • in utero embryonic development • fertilization • receptor-mediated endocytosis • positive regulation of cholesterol storage • lipid metabolism • cholesterol metabolic process • cholesterol transport • regulation of cholesterol biosynthetic process • lipid transport • nervous system development • leukocyte migration • response to carbohydrate • retinoid metabolic process • steroid metabolic process • triglyceride mobilization • lipid catabolic process • response to lipopolysaccharide • positive regulation of macrophage derived foam cell differentiation • cellular response to prostaglandin stimulus • response to virus • positive regulation of lipid storage • cellular response to tumor necrosis factor • response to selenium ion • flagellated sperm motility • positive regulation of gene expression • response to organic substance • cholesterol homeostasis • spermatogenesis • triglyceride catabolic process • cholesterol efflux • post-embryonic development • lipoprotein transport • toll-like receptor signaling pathway • response to estradiol • membrane organization • chylomicron remodeling • low-density lipoprotein particle remodeling • chylomicron assembly • very-low-density lipoprotein particle assembly • chylomicron remnant clearance • low-density lipoprotein particle clearance • very-low-density lipoprotein particle clearance • lipoprotein metabolic process • lipoprotein biosynthetic process • lipoprotein catabolic process • post-translational modification • cellular protein metabolic process • transport
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
Entrez
338
238055
Ensembl
ENSG00000084674
ENSMUSG00000020609
UniProt
P04114
E9Q414
RefSeq (mRNA)
NM_000384
NM_009693
RefSeq (protein)
NP_000375
NP_033823
Location (UCSC)
Chr 2: 21 – 21.04 Mb
Chr 12: 7.98 – 8.02 Mb
PubMed search
[3]
[4]
Wikidata
View/Edit Human
View/Edit Mouse
Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene.
Contents
1Function
2Genetic disorders
3Mouse studies
4Molecular biology
5Clinical significance
5.1Benefits
5.1.1Role in innate immune system
5.2Adverse effects
5.2.1Role in insulin resistance
5.2.2Role in lipoproteins and atherosclerosis
6Interactions
7Interactive pathway map
8Regulation
9RNA editing
9.1Type
9.2Location
9.3Regulation
9.4Conservation
9.5Consequences
9.5.1Structure
9.5.2Function
10See also
11References
12Further reading
13External links
Function
Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, IDL, and LDL particles (LDL - known commonly by the misnomer "bad cholesterol" when in reference to both heart disease and vascular disease in general), which is responsible for carrying fat molecules (lipids), including cholesterol, around the body (within the water outside cells) to all cells within all tissues. While all the functional roles of ApoB within the LDL (and all larger) particles remain somewhat unclear, it is the primary organizing protein (of the entire complex shell enclosing/carrying fat molecules within) component of the particles and is absolutely required for the formation of these particles. What is also 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 indicates fat carrying particles are ready to enter any cells with ApoB receptors and deliver fats carried within into the cells).
Through mechanisms only partially understood, high levels of ApoB, especially associated with the higher LDL particle concentrations, are the primary driver of plaques that cause vascular disease (atherosclerosis), commonly first becoming obviously symptomatic as heart disease, stroke & many other body wide complications after decades of progression. There is considerable evidence that concentrations of ApoB[5][6] and especially the NMR assay[7] (specific for LDL-particle concentrations) are superior indicators of vascular/heart disease driving physiology than either total cholesterol or LDL-cholesterol (as long promoted by the NIH starting in the early 1970s). However, primarily for historic cost/complexity reasons, cholesterol, and estimated LDL-cholesterol by calculation, remains the most commonly promoted lipid test for the risk factor of atherosclerosis. ApoB is routinely measured using immunoassays such as ELISA or nephelometry. Refined and automated NMR methods allow measurement distinctions between the many different ApoB particles.
Genetic disorders
High levels of ApoB are related to heart disease.
Hypobetalipoproteinemia is a genetic disorder that can be caused by a mutation in the ApoB gene, APOB. Abetalipoproteinaemia is usually caused by a mutation in the MTP gene, MTP.
Mutations in gene APOB100 can also cause familial hypercholesterolemia, a hereditary (autosomal dominant) form of metabolic disorder Hypercholesterolemia.
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".[8] 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.[9]
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.[10] ApoB-100 is the largest of the apoB group of proteins, consisting of 4563 amino acids.[10] 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.[citation needed] Alternatively, there is some evidence that a cis-acting element several thousand bp upstream determines which isoform is produced.[citation needed]
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 absorbed, ApoB48 returns to the liver as part of the chylomicron remnant, where it is endocytosed and degraded.
Clinical significance
Benefits
Role in innate immune system
Very low-density lipoproteins and low-density lipoproteins interfere with the quorum sensing system that upregulates genes required for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding ApoB, to a S. aureus autoinducer pheromone, preventing signaling through its receptor. Mice deficient in ApoB are more susceptible to invasive bacterial infection.[11]
Adverse effects
Role in insulin resistance
Overproduction of apolipoprotein B can result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver.[12]
Role in lipoproteins and atherosclerosis
ApoB100 is found in lipoproteins originating from the liver (VLDL, IDL, LDL[13]). 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, they are a far better predictor of it than are LDL-C concentrations [14][15]. Reason: LCL-C does not reflect actual particle concentrations & cholesterol cannot dissolve or move (in water) without particles to carry it. A simple way to understand this observation is the fact that ApoB100, one per particle, reflects actual lipoprotein particle concentration (independent of their cholesterol, or other lipid content). In this way, one can understand that the number of ApoB100-containing lipoprotein particles which can carry lipids into the artery walls is a key determinant, driver 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 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 the 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 as its ability both to recruit immune effector cells and to promote platelet activation.
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.[16] In the general population this remains unclear although in a recent study ApoB was the strongest risk marker for cardiovascular events.[17] A small study suggests that added to fluvastatin treatment, omega 3 fatty acids daily, containing 460 mg of E-EPA and 380 mg of E-DHA (ethyl esters), may lower ApoB48 in hyperlipemic type 2 diabetics.[18]
Interactions
ApoB has been shown to interact with apo(a),[19] PPIB,[20] Calcitonin receptor[20][21] and HSP90B1.[20][21] Interaction of ApoB with proteoglycans, collagen, and fibronectin is believed to cause atherosclerosis.[22][23]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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Statin Pathway edit
^The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
Regulation
The expression of APOB is regulated by cis-regulatory elements in the APOB 5′ UTR and 3′ UTR.[24]
RNA editing
The mRNA of this protein is subject to Cytidine to Uridine (C to U) site-specific RNA editing. ApoB100 and ApoB48 are encoded by the same gene, however, the differences in the translated proteins are not due to alternative splicing but are due to the tissue-specific RNA editing event.
ApoB mRNA editing was the first example of editing observed in vertebrates.[25] Editing of ApoB mRNA occurs in all placental mammals.[26] Editing occurs post transcriptionally as the nascent polynucleotides do not contain edited nucleosides.[27]
Type
C to U editing of ApoB mRNA requires an editing complex or holoenzyme (editosome) consisting of the C to U-editing enzyme Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (ApoBEC-1) as well as other auxiliary factors. ApoBEC-1 is a protein that in humans is encoded by the APOBEC1 gene.[28][1]It is a member of the cytidine deaminase family. ApoBEC-1 alone is not sufficient for the editing of ApoB mRNA [29] and requires at least one of these auxiliary factors, APOBEC1 complementation factor (A1CF)[30] for editing to occur. A1CF contains 3 non identical repeats. It acts as the RNA binding subunit and directs ApoBEC-1 to the ApoB mRNA downstream of the edited cytidine.[31] Other auxiliary factors are known to be part of the holoenzyme. Some of these proteins have been identified. these are CUG binding protein 2 (CUGBP2),[32] SYNCRIP (glycine-arginine-tyrosine-rich RNA binding protein, GRY-RBP),[33] heterogenous nuclear ribonucleoprotein (hnRNP)-C1,[34] ApoBEC-1 binding protein (ABBP)1, ABBP2,[35] KH-type splicing regulatory binding protein (KSRP), Bcl-2-associated anthogene 4 (BAG4),[36] and auxiliary factor (AUX)240.[37] All these proteins have been identified using detection assays and have all been demonstrated to interact with either ApoBEC-1, A1CF, or ApoB RNA. The function of these auxiliary proteins in the editing complex are unknown. As well as editing ApoB mRNA, the ApoBEC-1 editsome also edits the mRNA of NF1. mRNA editing of ApoB mRNA is the best defined example of this type of C to U RNA editing in humans.
Location
Despite being a 14,000 residue long transcript, a single cytidine is targeted for editing. Within the ApoB mRNA a sequence consisting of 26 nucleotides necessary for editing is found. This is known as the editing motif. These nucleotides (6662–6687) were determined to be essential by site specific mutagenesis experiments.[38] An 11 nucleotide portion of this sequence 4–5 nucleotides downstream from the editing site is an important region known as the mooring sequence.[39] A region called the spacer element is found 2–8 nucleotides between the edited nucleoside and this mooring sequence.[40] There is also a regulatory sequence 3′ to the editing site. The active site of ApoBEC-1, the catalytic component of the editing holoenzyme is thought to bind to an AU rich region of the mooring sequence with the aid of ACF in binding the complex to the mRNA.[41]
The edited cytidine residue is located at nucleotide 6666 located in exon 26 of the gene. Editing at this site results in a codon change from a Glutamine codon (CAA) to an inframe stop codon (UAA).[25] Computer modelling has detected for editing to occur,the edited Cytidine is located in a loop.[39] The selection of the edited cytidine is also highly dependent on this secondary structure of the surrounding RNA. There are also some indications that this loop region is formed between the mooring sequence and the 3′ regulatory region of the ApoB mRNA.[42] The predicted secondary structure formed by ApoB mRNA is thought to allow for contact between the residue to be edited and the active site of APOBEC1 as well as for binding of ACF and other auxiliary factors associated with the editosome.
Regulation
Editing of ApoB mRNA in humans is tissue regulated, with ApoB48 being the main ApoB protein of the small intestine in humans. It occurs in lesser amounts in the colon, kidney and stomach along with the non edited version.[43]
Editing is also developmentally regulated with the non edited version only being translated early in development but the edited form increases during development in the tissues where editing can occur.[44][45]
Editing levels of ApoB mRNA have been shown to vary in response to changes in diet. exposure to alcohol and hormone levels.[46][47][48]
Conservation
ApoB mRNA editing also occurs in mice, and rats. In contrast to humans editing occurs in liver in mice and rats up to a frequency of 65%.[49] It has not been observed in birds or lesser species.[50]
Consequences
Structure
Editing results in a codon change creating an in-frame stop codon leading to translation of a truncated protein, ApoB48. This stop codon results in the translation of a protein that lacks the carboxyl terminus which contains the protein's LDLR binding domain. The full protein ApoB100 which has nearly 4500 amino acids is present in VLDL and LDL. Since many parts of ApoB100 are in an amphipathic condition, the structure of some of its domains is dependent on underlying lipid conditions. However, it is known to have the same overall folding in LDL having five main domains. Recently the first structure of LDL at human body temperature in native condition has been found using cryo-electron microscopy at a resolution of 16 Angstrom.[51] The overall folding of ApoB-100 has been confirmed and some heterogeneity in the local structure of its domains have been mapped.
Function
Editing is restricted to those transcripts expressed in the small intestine. This shorter version of the protein has a function specific to the small intestine. The main function of the full length liver expressed ApoB100 is as a ligand for activation of the LDL-R. However, editing results in a protein lacking this LDL-R binding region of the protein. This alters the function of the protein and the shorter ApoB48 protein as specific functions relative to the small intestine.
ApoB48 is identical to the amino-terminal 48% of ApoB100.[52] The function of this isoform is in fat absorption of the small intestine and is involved in the synthesis, assembly and secretion of chylomicrons. These chylomicrons transport dietary lipids to tissues while the remaining chylomicrons along with associated residual lipids are in 2–3 hours taken up by the liver via the interaction of apolipoprotein E (ApoE) with lipoprotein receptors. It is the dominant ApoB protein in the small intestine of most mammals. It is a key protein in the exogenous pathway of lipoprotein metabolism. Intestinal proteins containing ApoB48 are metabolized to chylomicron remnant particles which are taken up by remnant receptors.
See also
Apolipoprotein A1
ACAT2
Cardiovascular disease
Lipid metabolism
References
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^ abcGRCm38: Ensembl release 89: ENSMUSG00000020609 - Ensembl, May 2017
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^Chan L, Chang BH, Nakamuta M, Li WH, Smith LC (March 1997). "Apobec-1 and apolipoprotein B mRNA editing". Biochim. Biophys. Acta. 1345 (1): 11–26. doi:10.1016/S0005-2760(96)00156-7. PMID 9084497.
^Chan L (January 1993). "RNA editing: exploring one mode with apolipoprotein B mRNA". BioEssays. 15 (1): 33–41. doi:10.1002/bies.950150106. PMID 8466474.
^Tarugi P, Albertazzi L, Nicolini S, Calandra S (March 1990). "Absence of apolipoprotein B-48 in the chick, Gallus domesticus". J. Lipid Res.31 (3): 417–427. PMID 2341807.
^Kumar V, Butcher SJ, Öörni K, Engelhardt P, Heikkonen J, Kaski K, Ala-Korpela M, Kovanen PT (May 2011). "Three-Dimensional cryoEM Reconstruction of Native LDL Particles to 16Å Resolution at Physiological Body Temperature". PLoS ONE. 6 (5): e18841. Bibcode:2011PLoSO...618841K. doi:10.1371/journal.pone.0018841. PMC 3090388. PMID 21573056.
^Knott TJ, Pease RJ, Powell LM, Wallis SC, Rall SC, Innerarity TL, Blackhart B, Taylor WH, Marcel Y, Milne R (1986). "Complete protein sequence and identification of structural domains of human apolipoprotein B". Nature. 323 (6090): 734–738. Bibcode:1986Natur.323..734K. doi:10.1038/323734a0. PMID 3773997.
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:10.1371/journal.ppat.0030108. PMC 1959368. PMID 17784784.
External links
Database of RNA editing (DARNED).
Applied Research on Apolipoprotein-B
Human APOB genome location and APOB gene details page in the UCSC Genome Browser.
v
t
e
Lipids: lipoprotein particle metabolism
Lipoprotein particle classes and subclasses
delivery of TGs: Chylomicron
VLDL
delivery of C and CE: IDL
LDL
lb LDL
sd LDL
Lp(a)
HDL
Remnant cholesterol
Apolipoproteins
APOA
1
2
4
5
APOB
APOC
1
2
3
4
APOD
APOE
APOH
SAA
SAA1
Extracellular enzymes
LCAT
LIPC
LPL
Lipid transfer proteins
CETP
MTTP
PLTP
Cell surface receptors
HDL: SCARB1
IDL: LRP
LRP1
LRP1B
LRP2
LRP3
LRP4
LRP5
LRP5L
LRP6
LRP8
LRP10
LRP11
LRP12
LDL: LDLR
LRPAP1
ATP-binding cassette transporter
ABCA1
ABCG5
ABCG8
UpToDate Contents
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… intrahepatically from apolipoprotein (a) and LDL . Apo(a) links to apolipoprotein B-100 on the surface of LDL by disulfide bridges. The formation of apo(a):apo B complexes requires an LDL particle of a certain …
…including further subfractions of LDL based on density and measurement of various apolipoproteins (apo) A-1 and B. There are numerous studies examining the power of each of these various lipoproteins in predicting…
…g/day) can lower Lp(a) levels by as much as 38 percent . In addition, nicotinic acid lowers LDL-C, apo B-100, small LDL, and triglycerides and raises high-density lipoprotein-cholesterol (HDL-C) levels. …
…total cholesterol, low density lipoprotein cholesterol (LDL-C), triglycerides, and apolipoprotein (apo) B. Premature atherosclerotic cardiovascular disease (ASCVD) is not uncommon. There is overlap with …
…administer memantine concurrently. For patients with limited stage (stage I or II) diffuse large B cell non-Hodgkin lymphoma (DLBCL) with no adverse features, we suggest four cycles of R-CHOP (rituximab …
English Journal
Zygophyllum album saponins prevent atherogenic effect induced by deltamethrin via attenuating arterial accumulation of native and oxidized LDL in rats.
Feriani A, Tir M, Hachani R, Gómez-Caravaca AM, Contreras MDM, Taamalli A, Talhaoui N, Segura-Carretero A, Ghazouani L, Mufti A, Tlili N, El Feki A, Harrath AH, Allagui MS.
Ecotoxicology and environmental safety. 2020 Apr;193()110318.
The current study aimed to examine, for the first time, the relationship between exposure to deltamethrin (DLM) and atherogenic lipid profile disorders in adult Wistar rats, as well as, to verify the mechanism of the beneficial role of Zygophyllum album leaves extracts (ZALE). The experimental study
The clinical and laboratory investigation of dysbetalipoproteinemia.
Boot CS, Luvai A, Neely RDG.
Critical reviews in clinical laboratory sciences. 2020 Apr;()1-12.
Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is a potentially underdiagnosed inherited dyslipidemia associated with greatly increased risk of coronary and peripheral vascular disease. The mixed hyperlipidemia observed in this disorder usually responds well to appropriate medical t
Role of apolipoprotein E in electronegative low-density lipoprotein-induced mitochondrial dysfunction in cardiomyocytes.
Chen WY, Chen YF, Chan HC, Chung CH, Peng HY, Ho YC, Chen CH, Chang KC, Tang CH, Lee AS.
Metabolism: clinical and experimental. 2020 Apr;()154227.
L5, a highly electronegative subtype of low-density lipoprotein (LDL), is likely associated with the development of atherosclerosis and cardiovascular diseases. Normal LDL is composed mainly of apolipoprotein (Apo) B, but L5 has additional proteins such as ApoE. We previously demonstrated that L5 in
Evaluation of apocynin in vitro on high glucose-induced oxidative stress on tenocytes
Kurosawa T.,Mifune Y.,Inui A.,Nishimoto H.,Ueda Y.,Kataoka T.,Yamaura K.,Mukohara S.,Kuroda R.
Bone & Joint Research 9(1), 23-28, 2020-01
… regular glucose with apocynin (RG apo+); … high glucose with apocynin (HG apo+); … and high glucose without apocynin (HG apo-). … Results Expression of NOX1, NOX4, and IL-6 mRNA in the HG groups was significantly higher compared with that in the RG groups, and NOX1, NOX4, and IL-6 mRNA expression in the HG apo+ group was significantly lower compared with that in the HG apo- group. …
Rasagiline Pharmacokinetics are affected by cytochrome P-450 1A2 genetic variants in different doses
Bilal Rabiea,Saud Naseem,Riffat Sualeha
日本薬理学会年会要旨集 93(0), 2-O-039, 2020
… The plasma concentrations were determined using High performance liquid chromatography and pharmacokinetic variables were calculated using APO Pharmacologica software. …
Apo B-48は、Chylomicronに特異的な構造タンパク質で 食事等に由来する外因性脂質輸送の観察に役立ちます。 食後のTGとApo B-48，Total Apo Bの変化 Nakano,T. et al. Ann Clin Biochem, Vol.48, p57-64, Jan 2011.から作図
More than 120 mutations in the APOB gene have been found to cause familial hypobetalipoproteinemia (FHBL), a disorder that impairs the body's ability to absorb and transport fat. Most APOB gene mutations that cause FHBL lead to the production of apolipoprotein B that is abnormally short. ...