Apolipoprotein B (ApoB) is a
protein that in humans is encoded by the
gene.
Function
Apolipoprotein B is the primary
apolipoprotein of
chylomicrons,
VLDL,
Lp(a)
Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart ...
,
IDL
IDL may refer to:
Computing
* Interface description language, any computer language used to describe a software component's interface
** IDL specification language, the original IDL created by Lamb, Wulf and Nestor at Queen's University, Canada
...
, and
LDL particles (LDL—commonly known as "bad
cholesterol" when in reference to both
heart disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
and
vascular disease in general), which is responsible for carrying
fat molecules (
lipids), including
cholesterol, around the body 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
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
,
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
and 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
Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
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
A nephelometer or aerosol photometer is an instrument for measuring the concentration of suspended particulates in a liquid or gas colloid. A nephelometer measures suspended particulates by employing a light beam (source beam) and a light detec ...
. 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
Hypobetalipoproteinemia is a disorder consisting of low levels of LDL cholesterol or apolipoprotein B, below the 5th percentile. The patient can have hypobetalipoproteinemia and simultaneously have high levels of HDL cholesterol.
Notably, in peopl ...
is a
genetic disorder that can be caused by a mutation in the ApoB gene, ''APOB''.
Abetalipoproteinaemia
Abetalipoproteinemia (also known as: Bassen-Kornzweig syndrome, microsomal triglyceride transfer protein deficiency disease, MTP deficiency, and betalipoprotein deficiency syndrome) is a disorder that interferes with the normal absorption of fat ...
is usually caused by a mutation in the MTP gene, ''MTP''.
Mutations in gene ''APOB100'' can also cause
familial hypercholesterolemia
Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL cholesterol), in the blood and early cardiovascular disease. The most common mutatio ...
, a hereditary (autosomal dominant) form of metabolic disorder
hypercholesterolemia.
Mouse studies
Most relevant information regarding mouse ApoB homologue, mApoB, has come from
mouse
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
studies. Mice overexpressing mApoB have increased levels of LDL and decreased levels of
HDL. 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
Plasma or plasm may refer to:
Science
* Plasma (physics), one of the four fundamental states of matter
* Plasma (mineral), a green translucent silica mineral
* Quark–gluon plasma, a state of matter in quantum chromodynamics
Biology
* Blood pla ...
in 2 main isoforms, ApoB48 and ApoB100. The first is synthesized exclusively by the
small intestine
The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
, 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
The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface 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
''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...
'' infection. The mechanism of antagonism entails binding ApoB, to a ''S. aureus''
autoinducer
Autoinducers are signaling molecules that are produced in response to changes in cell-population density. As the density of quorum sensing bacterial cells increases so does the concentration of the autoinducer. Detection of signal molecules by ba ...
pheromone, preventing signaling through its receptor. Mice deficient in ApoB are more susceptible to invasive bacterial infection.
Adverse effects
Role in insulin resistance
Overproduction of apolipoprotein B can result in lipid-induced
endoplasmic reticulum stress Beta cells are heavily engaged in the synthesis and secretion of insulin. They are therefore particularly sensitive to endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR). Severe or prolonged episodes of ER st ...
and
insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
in the liver.
Role in lipoproteins and atherosclerosis
ApoB100 is found in
lipoproteins originating from the liver (
VLDL,
IDL
IDL may refer to:
Computing
* Interface description language, any computer language used to describe a software component's interface
** IDL specification language, the original IDL created by Lamb, Wulf and Nestor at Queen's University, Canada
...
,
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, they are a far better predictor of it than are LDL-C concentrations. Reason: LDL-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, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger heart attacks and stroke.
Foam cells are fat-laden cells with a M2 macrophage-like ...
". 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. (
ApoA1
Apolipoprotein AI (ApoA-I) is a protein that in humans is encoded by the ''APOA1'' gene. As the major component of HDL particles, it has a specific role in lipid metabolism.
Structure
''APOA1'' is located on chromosome 11, with its specific lo ...
is the major HDL protein.
) In the general population this remains unclear although in a recent study ApoB was the strongest risk marker for cardiovascular events.
Interactions
ApoB has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
apo(a),
PPIB,
Calcitonin receptor and
HSP90B1.
Interaction of ApoB with
proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to whic ...
s,
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
, and
fibronectin is believed to cause
atherosclerosis.
Interactive pathway map
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 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.
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.
t is a member of the
cytidine deaminase
Cytidine deaminase is an enzyme that in humans is encoded by the ''CDA'' gene.
This gene encodes an enzyme involved in pyrimidine salvaging. The encoded protein forms a homotetramer that catalyzes the irreversible hydrolytic deamination of cytid ...
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),
heterogeneous nuclear ribonucleoprotein (hnRNP)-C1 (
HNRNPC
Heterogeneous nuclear ribonucleoproteins C1/C2 is a protein that in humans is encoded by the ''HNRNPC'' gene.
It is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increase risk of birth defects in these ART.
Fu ...
),
ApoBEC-1 binding protein ABBP1 (''
HNRNPAB
Heterogeneous nuclear ribonucleoprotein A/B, also known as HNRNPAB, is a protein which in humans is encoded by the ''HNRNPAB'' gene. Although this gene is named ''HNRNPAB'' in reference to its first cloning as an RNA binding protein with similarit ...
''), ABBP2,
KH-type splicing regulatory binding protein (''
KHSRP''), Bcl-2-associated athanogene 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
Neurofibromin 1 (''NF1'') is a gene in humans that is located on chromosome 17. ''NF1'' codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. ''N ...
. 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, and 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 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.
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
The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...
. 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.
The function of this isoform is in fat absorption of the small intestine and is involved in the synthesis, assembly and secretion of
chylomicrons
Chylomicrons (from the Greek χυλός, chylos, meaning ''juice'' (of plants or animals), and micron, meaning ''small particle''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85 ...
. 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
Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease.
APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
(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
Acetyl-CoA acetyltransferase, cytosolic, also known as cytosolic acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ''ACAT2'' (acetyl-Coenzyme A acetyltransferase 2) gene
Acetyl-Coenzyme A acetyltransferase 2 is an acetyl-C ...
*
Cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
*
Lipid metabolism
References
Further reading
*
*
*
*
External links
Database of RNA editing (DARNED)
Applied Research on Apolipoprotein-B*
{{Lipoproteins
Apolipoproteins