apolipoprotein B

WordNet

1. the 2nd letter of the Roman alphabet (同)b
2. the blood group whose red cells carry the B antigen (同)type_B, group B

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/08/07 17:27:34」(JST)

wiki en

[Wiki en表示]

APOB
Identifiers
Aliases	APOB, FLDB, LDLCQ4, apoB-100, apoB-48, apolipoprotein B
External IDs	OMIM: 107730 MGI: 88052 HomoloGene: 328 GeneCards: APOB
Gene ontology Molecular function • protein binding • lipid binding • lipid transporter activity • cholesterol transporter activity • lipase binding • low-density lipoprotein particle receptor binding • phospholipid binding • heparin binding Cellular component • early endosome • chylomicron remnant • vesicle lumen • endoplasmic reticulum • endosome membrane • extracellular region • mature chylomicron • endoplasmic reticulum lumen • vesicle membrane • endosome lumen • intermediate-density lipoprotein particle • clathrin-coated endocytic vesicle membrane • endoplasmic reticulum membrane • extracellular exosome • endocytic vesicle lumen • neuronal cell body • cytoplasm • chylomicron • very-low-density lipoprotein particle • low-density lipoprotein particle • endoplasmic reticulum exit site • extracellular space • smooth endoplasmic reticulum • cytosol • plasma membrane • lysosomal lumen • intracellular membrane-bounded organelle Biological process • artery morphogenesis • in utero embryonic development • fertilization • receptor-mediated endocytosis • positive regulation of cholesterol storage • lipid metabolic process • 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 protein modification • cellular protein metabolic process • transport Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
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
Wikidata
View/Edit Human View/Edit Mouse

Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene.

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 remains 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 and especially the NMR assay (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". 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.

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. ApoB-100 is the largest of the apoB group of proteins, consisting of 4563 amino acids. 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 absorbed, ApoB48 returns to the liver as part of the chylomicron remnant, where it is endocytosed and degraded.

Clinical significance

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.

Role in insulin resistance

Overproduction of apolipoprotein B can result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver.

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.

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. In the general population this remains unclear although in a recent study ApoB was the strongest risk marker for cardiovascular events. 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.

Interactions

ApoB has been shown to interact with apo(a), PPIB, Calcitonin receptor and HSP90B1. Interaction of ApoB with proteoglycans, collagen, and fibronectin is believed to cause atherosclerosis.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

[[File:

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

|px|alt=Statin Pathway edit]]

File:StatinPathway_WP430.png

Statin Pathway edit

Regulation

The expression of APOB is regulated by cis-regulatory elements in the APOB 5' UTR and 3' UTR.

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 is not due to alternative splicing but is due to the tissue specific RNA editing event. ApoB mRNA editing was the first example of editing observed in vertebrates. Editing of ApoB mRNA occurs in all placental mammals. Editing occurs post transcriptionally as the nascent polynucleotides do not contain edited nucleosides.

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.[1]It is a member of the cytidine deaminase family. ApoBEC-1 alone is not sufficient for the editing of ApoB mRNA and requires at least one of these auxiliary factors, APOBEC1 complementation factor (A1CF) 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. 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), SYNCRIP (glycine-arginine-tyrosine-rich RNA binding protein, GRY-RBP), heterogenous nuclear ribonucleoprotein (hnRNP)-C1, ApoBEC-1 binding protein (ABBP)1, ABBP2, KH-type splicing regulatory binding protein (KSRP), Bcl-2-associated anthogene 4 (BAG4), and auxiliary factor (AUX)240. 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. An 11 nucleotide portion of this sequence 4-5 nucleotides downstream from the editing site is an important region known as the mooring sequence. A region called the spacer element is found 2-8 nucleotides between the edited nucleoside and this mooring sequence. 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. 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). Computer modelling has detected for editing to occur,the edited Cytidine is located in a loop. 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. 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. 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. Editing levels of ApoB mRNA have been shown to vary in response to changes in diet. exposure to alcohol and hormone levels.

Conservation

ApoB mRNA editing also occurs in mice, rats.In contrast to humans editing occurs in liver in mice and rats up to a frequency of 65%. It has not been observed in birds or lesser species.

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 which lacks the carboxyl terminus which contains the protein's LDLR binding domain. The full protein ApoB100 which has nearly 4500 amino acid is present in VLDL and LDL. Since many parts of ApoB100 are in amphipathic condition, the structure of some of its domains are dependent on underlying lipid condition. However it is known to have same over all folding in LDL having five main domains. Recently first structure of LDL at human body temperature in native condition has been found using cryo-electron microscopy at a resolution of 16 Angstrom. 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 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. 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 metabolised to chylomicron remnant particles which are taken up by remnant receptors.

See also

• Apolipoprotein A1
• ACAT2
• Cardiovascular disease
• Lipid metabolism

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. PMC 1959368 . PMID 17784784. doi:10.1371/journal.ppat.0030108. 

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.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. リポ​蛋白​の​分類​、​代謝​、​および​アテローム​性動脈硬化症​における​役割​ lipoprotein classification metabolism and role in atherosclerosis
• 2. 脂質疾患​に​対​する​スクリーニング​ screening for lipid disorders
• 3. リポ​蛋白​a​と​心血管疾患​ lipoprotein a and cardiovascular disease
• 4. LDL​コレステロール​代謝​の​遺伝性疾患​ inherited disorders of ldl cholesterol metabolism
• 5. 小児​における​脂質異常症​の​定義​および​スクリーニング​ definition and screening for dyslipidemia in children

English Journal

• Marine omega-3 fatty acid supplementation in non-alcoholic fatty liver disease: Plasma proteomics in the randomized WELCOME* trial.

• Manousopoulou A, Scorletti E, Smith DE, Teng J, Fotopoulos M, Roumeliotis TI, Clough GF, Calder PC, Byrne CD, Garbis SD.
• Clinical nutrition (Edinburgh, Scotland). 2019 Aug;38(4)1952-1955.
• Non-alcoholic fatty liver disease (NAFLD) is a liver condition characterised by liver fat accumulation and often considered to be the liver manifestation of metabolic syndrome. The aim of this study was to examine in patients with NAFLD the system-wide effects of treatment with docosahexaenoic acid
• PMID 30172659

• Cost-effective production of recombinant peptides in Escherichia coli.

• Gaglione R, Pane K, Dell'Olmo E, Cafaro V, Pizzo E, Olivieri G, Notomista E, Arciello A.
• New biotechnology. 2019 Jul;51()39-48.
• Among bioactive peptides, cationic antimicrobial peptides (AMPs), also referred to as host defence peptides (HDPs), are valuable tools to treat infections, being able to kill a wide variety of microbes directly and/or modulate host immunity. HDPs have great therapeutic potential against antibiotic-r
• PMID 30790718

• Hypercholesterolemia in young adult APOE mice alters epidermal lipid composition and impairs barrier function.

• Martins Cardoso R, Creemers E, Absalah S, Gooris GS, Hoekstra M, Van Eck M, Bouwstra JA.
• Biochimica et biophysica acta. Molecular and cell biology of lipids. 2019 Jul;1864(7)976-984.
• Long-term exposure to hypercholesterolemia induces the development of skin xanthoma's characterized by the accumulation of lipid-laden foam cells in humans and in mice. Early skin changes in response to hypercholesterolemia are however unknown. In this study, we investigated the skin lipid compositi
• PMID 30905828

Japanese Journal

• リポタンパク関連臨床指標の進歩と課題 (代謝) -- (臨床分野での進歩)

• Annual review. 糖尿病・代謝・内分泌, 126-135, 2016
• NAID 40020739719

• Multifarious effects of 17-β-estradiol on apolipoprotein E receptors gene expression during osteoblast differentiation <i>in vitro </i>

• BioScience Trends advpub(0), 2016
• NAID 130005129193

Related Links

• Apo B: The Test | Apolipoprotein B - Blood, Urine & Other ...

Proceeds from website advertising help sustain Lab Tests Online. AACC is a not-for-profit organization and does not endorse non-AACC products and services. ... The apolipoprotein B (apo B) test is used, along with other lipid tests, to help determine an individual's risk of developing ...

• APOB - apolipoprotein B - Genetics Home Reference

The official name of this gene is “apolipoprotein B.” APOB is the gene's official symbol. The APOB gene is also known by other names, listed below. Read more about gene names and symbols on the About page.

Related Pictures

---

★リンクテーブル★

リンク元	「アポリポ蛋白B」「アポリポタンパク質B」「アポリポ蛋白質B」「アポリポタンパクB」「apoB」
拡張検索	「apolipoprotein B familial hypobetalipoproteinemia」「apolipoprotein B-48」
関連記事	「B」「apolipoprotein」「apolipoproteins」

「アポリポ蛋白B」

　　[★]

英

apolipoprotein B、apoB、apo B

関

アポリポタンパクB、アポリポタンパク質B、アポリポ蛋白質B、アポB

「アポリポタンパク質B」

　　[★]

英

apolipoprotein B、apoB、apo B

関

アポリポ蛋白B、アポリポタンパクB、アポリポ蛋白質B、アポB

「アポリポ蛋白質B」

　　[★]

英

apolipoprotein B

関

アポリポ蛋白B、アポリポタンパクB、アポリポタンパク質B

「アポリポタンパクB」

　　[★]

英

apolipoprotein B

関

アポリポ蛋白B、アポリポタンパク質B、アポリポ蛋白質B

「apoB」

　　[★]

• アポリポタンパク質B、アポリポ蛋白B、アポB

関

apo B、apolipoprotein B

「apolipoprotein B familial hypobetalipoproteinemia」

　　[★] 家族性アポリポ蛋白B低βリポ蛋白血症、家族性アポリポタンパク質B低βリポタンパク質血症

「apolipoprotein B-48」

　　[★]

ア・リ・タンパク質B-48

「B」

　　[★]

• 気管分岐部下緑
• 補体のalternative pathwayに関わる蛋白質

• Mg2+存在下でC3, B, Dが反応してC3bBbとなり、これがC3転換酵素(C3bBb)あるいはC5転換酵素(C3bBb3b)を形成する。これらはP(properdin)と結合して活性化し、それぞれC3、C5を活性化する

　 　

「apolipoprotein」

　　[★]

• アポリポタンパク質、アポリポ蛋白質、アポリポタンパク、アポリポ蛋白、アポリポプロテイン

関

apo

「apolipoproteins」

　　[★]

同

apolipoprotein

同

apolipoprotein