Apolipoprotein B
Apolipoprotein B is the primary apolipoprotein
Apolipoproteins are proteins that bind lipids to form lipoproteins and transport the lipids through the lymphatic and circulatory systems....

 of low-density lipoproteins (LDL or "bad cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

"), which is responsible for carrying cholesterol to tissue
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

s. 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
Vascular disease
Vascular disease is a form of cardiovascular disease primarily affecting the blood vessels.Some conditions, such as angina and myocardial ischemia, can be considered both vascular diseases and heart diseases .Cigarette smoking is the major risk factor....

Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

), leading to heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...

. There is considerable evidence that levels of APOB are a better indicator of heart disease risk than total cholesterol or LDL. However, primarily for historic reasons, cholesterol, and more specifically, LDL-cholesterol, remains the primary lipid test for the risk factor of atherosclerosis.

Genetic disorders

High levels of APOB are related to heart disease.
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....

 is a genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....

 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
Familial hypercholesterolemia
Familial hypercholesterolemia is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein , in the blood and early cardiovascular disease...

, a hereditary (autosomal dominant) form of metabolic disorder Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...


Mouse studies

Most relevant information regarding mouse APOB homologue, mApoB, has come from mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

 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
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...

. Mice containing no functional copies of the gene are not viable.

Molecular biology

The protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 occurs in the plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 in 2 main isoforms, APOB48 and APOB100. The first is synthesized exclusively by the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

, the second by the liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

. Both isoforms are coded by APOB and by a single mRNA transcript larger than 16 kb. APOB48 is generated when a stop codon
Stop codon
In the genetic code, a stop codon is a nucleotide triplet within messenger RNA that signals a termination of translation. Proteins are based on polypeptides, which are unique sequences of amino acids. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide...

 (UAA) at residue 2153 is created by RNA editing
RNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...

. 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
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...

 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
LDL receptor
The Low-Density Lipoprotein Receptor is a mosaic protein of ~840 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100 which is embedded in the phospholipid outer layer of LDL particles...

 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 interfere with the quorum sensing
Quorum sensing
Quorum sensing is a system of stimulus and response correlated to population density. Many species of bacteria use quorum sensing to coordinate gene expression according to the density of their local population. In similar fashion, some social insects use quorum sensing to determine where to nest...

 system that upregulates genes required for invasive Staphylococcus aureus
Staphylococcus aureus
Staphylococcus aureus is a facultative anaerobic Gram-positive coccal bacterium. It is frequently found as part of the normal skin flora on the skin and nasal passages. It is estimated that 20% of the human population are long-term carriers of S. aureus. S. aureus is the most common species of...

 infection. The mechanism of antagonism entails binding Apolipoprotein B, to a S. aureus autoinducer
Autoinducers are chemical signaling molecules that are produced and used by bacteria participating in quorum sensing. Quorum sensing is a phenomenon that allows both Gram-negative and Gram-positive bacteria to sense one another and to regulate a wide variety of physiological activities. Such...

 pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection.

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
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called 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
Foam cells are cells in an atheroma derived from both macrophages and smooth muscle. In chronic hyperlipidemia, lipoproteins aggregate within the intima of blood vessels and become oxidized by the action of oxygen free radicals generated either by macrophages or endothelial 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
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

 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
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...


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. 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 fluvastatatin treatment, omega 3 fatty acids daily, containing 460 mg of E-EPA and 380 mg of E-DHA (ethyl esters), may lower apo B48 in hyperlipemic type 2 diabetics.


Apolipoprotein B has been shown to interact
Protein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with PPIB
Peptidyl-prolyl cis-trans isomerase B is an enzyme that in humans is encoded by the PPIB gene.-Interactions:PPIB has been shown to interact with Apolipoprotein B.-Further reading:...

, Calcitonin receptor
Calcitonin receptor
The calcitonin receptor is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism ....

 and HSP90B1
Heat shock protein 90kDa beta member 1 , known also as endoplasmin, gp96, grp94 and ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene....



The expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...

 of APOB is regulated by cis-regulatory element
Cis-regulatory element
A cis-regulatory element or cis-element is a region of DNA or RNA that regulates the expression of genes located on that same molecule of DNA . This term is constructed from the Latin word cis, which means "on the same side as". These cis-regulatory elements are often binding sites for one or...

s in the APOB 5' UTR
Apolipoprotein B (apoB) 5' UTR cis-regulatory element
The apolipoprotein B 5' UTR cis regulatory element is an RNA element located in the 5' UTR of the human apoB mRNA. This structured element increases translation of the apoB protein or a reporter gene....

 and 3' UTR.

RNA editing

The mRNA of this protein is subject to Cytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...

 to Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....

 (C to U) site specific RNA editing
RNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...

. 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 polypeptides do not contain edited nucleosides.


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
ACF (gene)
APOBEC1 complementation factor is a protein that in humans is encoded by the A1CF gene.-Interactions:ACF has been shown to interact with CUGBP2, SYNCRIP and APOBEC1.-Further reading:...

 (ACF) for editing to occur. ACF contains 3 non identicle 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), 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 protein 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
NF1 can refer to:* Neurofibromatosis type I, a genetic disorder* Neurofibromin 1, a protein associated with the disorder above* Nuclear factor 1, a transcription factor...

. mRNA editing of ApoB mRNA is the best defined example of this type of C to U RNA editing in humans.


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 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 editsome.


Editing of ApoB mRNA in humans is tissue regulated, with ApoB48 bring 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.


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.


Editing results in a codon change creating an in frame stop codon leading to translation of a truncated protein, APOB 48. 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 ApoB-100 which has nearly 4500 amino acid is present in VLDL and LDL. Since many parts of ApoB-100 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.


Editing is restricted to those transcripts expressed in the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

. This shorter version of the protein has a function specific to the small intestine. The main function of the full length liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 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
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...

(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 renant particles which are taken up by renant receptors.

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