Apolipoprotein B

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Apolipoprotein B
Identifiers
Symbols APOB ; FLDB; LDLCQ4
External IDs OMIM107730 MGI88052 HomoloGene328 ChEMBL: 4549 GeneCards: APOB Gene
RNA expression pattern
PBB GE APOB 205108 s at tn.png
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:
21.22 – 21.27 Mb
Chr 12:
7.98 – 8.02 Mb
PubMed search [1] [2]

Apolipoprotein B (ApoB) are the primary apolipoproteins of chylomicrons and low-density lipoproteins (LDL - known commonly by the misnomer "bad cholesterol" when in reference to heart disease), 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.[1][2] However, primarily for historic reasons, cholesterol, and more specifically, LDL-cholesterol, remains the primary lipid test for the risk factor of atherosclerosis.

Genetic disorders[edit]

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[edit]

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".[3] 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.[4]

Molecular biology[edit]

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.[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 digested, ApoB48 returns to the liver as part of the chylomicron remnant, where it is endocytosed and degraded.

Role in Innate Immune System[edit]

VLDL and LDL 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.[5]

Role in lipoproteins and atherosclerosis[edit]

ApoB100 is found in lipoproteins originating from the liver (VLDL, IDL, LDL[6]). 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.[7] In the general population this remains unclear although in a recent study ApoB was the strongest risk marker for cardiovascular events.[8] A small study suggests that added to fluvastatatin 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.[9]

Interactions[edit]

ApoB has been shown to interact with apo(a),[10] PPIB,[11] Calcitonin receptor[11][12] and HSP90B1.[11][12] Interaction of ApoB with proteoglycans, collagen, and fibronectin is believed to cause atherosclerosis.[13][14]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 

Regulation[edit]

The expression of APOB is regulated by cis-regulatory elements in the APOB 5' UTR and 3' UTR.[15]

RNA editing[edit]

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.[16] Editing of ApoB mRNA occurs in all placental Mammals.[17] Editing occurs post transcriptionally as the nascent polypeptides do not contain edited nucleosides.[18]

Type[edit]

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.[19][1]It is a member of the cytidine deaminase family. ApoBEC-1 alone is not sufficient for the editing of ApoB mRNA [20] and requires at least one of these auxiliary factors, APOBEC1 complementation factor (ACF)[21] for editing to occur. ACF 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.[22] 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),[23] glycine-arginine-tyrosine-rich RNA binding protein (GRY-RBP),[24] heterogenous nuclear ribonucleoprotein (hnRNP)-C1,[25] ApoBEC-1 binding protein (ABBP)1, ABBP2,[26] KH-type splicing regulatory binding protein (KSRP), Bcl-2-associated anthogene 4 (BAG4),[27] and auxiliary factor (AUX)240.[28] All these proteins have been identified using detection assays and have all been demonstrated to interact with either ApoBEC-1, ACF, 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[edit]

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.[29] An 11 nucleotide portion of this sequence 4-5 nucleotides downstream from the editing site is an important region known as the mooring sequence.[30] A region called the spacer element is found 2-8 nucleotides between the edited nucleoside and this mooring sequence.[31] 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.[32] 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).[16] Computer modelling has detected for editing to occur,the edited Cytidine is located in a loop.[30] 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.[33] 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 editsome. Another

Regulation[edit]

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.[34] 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.[35][36] Editing levels of ApoB mRNA have been shown to vary in response to changes in diet. exposure to alcohol and hormone levels.[37][38][39]

Conservation[edit]

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%.[40] It has not been observed in birds or lesser species.[41]

Consequences[edit]

Structure[edit]

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.[42] The overall folding of ApoB-100 has been confirmed and some heterogeneity in the local structure of its domains have been mapped.

Function[edit]

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.[43] 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[edit]

References[edit]

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  4. ^ Free text.png Farese Jr, RV; Ruland, SL; Flynn, LM; Stokowski, RP; Young, SG (1995). "Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in heterozygotes". Proceedings of the National Academy of Sciences of the United States of America 92 (5): 1774–8. Bibcode:1995PNAS...92.1774F. doi:10.1073/pnas.92.5.1774. PMC 42602. PMID 7878058. 
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Further reading[edit]

External links[edit]