Apolipoprotein E
Encyclopedia
Apolipoprotein E is a class of apolipoprotein
found in the chylomicron
and IDL
s that binds to a specific receptor
on liver cell
s and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.
of triglyceride
-rich lipoprotein
constituents. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease
. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease
(AD), immunoregulation
, and cognition
.
In the field of immune regulation, a growing amount of studies point to APOE's interaction with many immunological processes, including suppressing T cell
proliferation, macrophage
functioning regulation, lipid antigen presentation facilitation (by CD1
) to natural killer T cell
as well as modulation of inflammation
and oxidation.
Neonates with brain injuries and/or defects who also have abnormalities in the APOE gene may have an increased risk for cerebral palsy
, according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result in familial dysbetalipoproteinemia
, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol
and triglycerides are the consequence of impaired clearance of chylomicron
, VLDL and LDL remnants.
APOE is 299 amino acid
s long and transports lipoprotein
s, fat-soluble vitamins, and cholesterol
into the lymph system and then into the blood. It is synthesized principally in the liver
, but has also been found in other tissues such as the brain
, kidney
s, and spleen
. In the nervous system, non-neuronal cell types, most notably astroglia
and microglia
, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved low density lipoprotein receptor gene family
.
in a cluster with Apolipoprotein C1
and the Apolipoprotein C2. The APOE gene consists of four exons and three introns, totaling 3597 base pair
s. In melanocytic cells
APOE gene expression may be regulated by MITF
.
ApoE is polymorphic
with three major isoforms, ApoE2, ApoE3, ApoE4, which translate into three alleles of the gene:
These allelic forms differ from each other only by amino acid
substitutions at positions 112 and 158..On Entrez SNP these are positions 130 and 176, rs429358 and rs7412 respectively; Entrez SNP positioning and positioning within Ensembl Genome Browser as 130 and 176 being those of the preprotein, intracellular proteolysis shifting these to positions 112 and 158. The E2 allele has a Cys at positions 112 and 158 in the receptor-binding region of ApoE. The E3 allele is Cys-112 and Arg-158. The ApoE E4 allele is Arg at both positions. These have physiological consequences:
ApoE is a target gene of the liver X receptor
, a nuclear receptor
member that plays a role in the metabolism
regulation of cholesterol
, fatty acid
, and glucose
homeostasis
.
(AD) in a variety of ethnic groups. Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid
(insoluble protein aggregates). Alzheimer's Disease is characterized by build-ups of aggregates of the peptide
beta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. Some isoforms of ApoE are not as efficient as others at catalyzing these reactions. In particular, the isoform ApoE-ε4 is not very effective, resulting in increased vulnerability to Alzheimer's in individuals with that gene variation.
The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University
Linkage studies were followed by association analysis confirming the role of the ApoE4 allele.
Although 40-65% of AD patients have at least one copy of the 4 allele, ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease. Yet those with two e4 alleles have up to 20 times the risk of developing AD. There is also evidence that the ApoE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer's disease and at earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer's disease. The genotype ApoE 2,3 is considered at less risk for Alzheimer's disease. Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk similar to the ApoE 3,3 genotype.
The connection between neuron failure in Alzheimer's disease and depleted myelin cholesterol (via ApoE deficiency) has also been described in Cholesterol Depletion and consequently is a known statin
therapy adverse drug reaction.
Apolipoprotein
Apolipoproteins are proteins that bind lipids to form lipoproteins and transport the lipids through the lymphatic and circulatory systems....
found in the chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
and IDL
Intermediate density lipoprotein
Intermediate-density lipoproteins belong to the lipoprotein particle family and are formed from the degradation of very low-density lipoproteins. IDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream...
s that binds to a specific receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
on liver cell
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.
Function
APOE is essential for the normal catabolismCatabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
of triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
-rich lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
constituents. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD), immunoregulation
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, and cognition
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
.
In the field of immune regulation, a growing amount of studies point to APOE's interaction with many immunological processes, including suppressing T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
proliferation, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
functioning regulation, lipid antigen presentation facilitation (by CD1
CD1
For the album by Throbbing Gristle, see CD1 CD1 is a family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are related to the class I MHC molecules, and are involved in the presentation of lipid antigens to T cells...
) to natural killer T cell
Natural Killer T cell
Natural killer T cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. Many of these cells recognize the non-polymorphic CD1d molecule, an antigen-presenting molecule that binds self- and foreign lipids and glycolipids...
as well as modulation of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and oxidation.
Neonates with brain injuries and/or defects who also have abnormalities in the APOE gene may have an increased risk for cerebral palsy
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
, according to researchers at the Northwestern University Feinberg School of Medicine. Defects in APOE result in familial dysbetalipoproteinemia
Familial dysbetalipoproteinemia
Familial dysbetalipoproteinemia is a condition characterized by increased LDL, triglyceride, and cholesterol levels, and decreased HDL levels...
, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol
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...
and triglycerides are the consequence of impaired clearance of chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
, VLDL and LDL remnants.
APOE is 299 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long and transports lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
s, fat-soluble vitamins, and cholesterol
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...
into the lymph system and then into the blood. It is synthesized principally in the liver
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...
, but has also been found in other tissues such as the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, and spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
. In the nervous system, non-neuronal cell types, most notably astroglia
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
and microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved low density lipoprotein receptor gene family
Low density lipoprotein receptor gene family
The low density lipoprotein receptor gene family code for a class of structurally closely related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is...
.
Gene
The protein, ApoE, is mapped to chromosome 19Chromosome 19 (human)
125px|rightChromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active...
in a cluster with Apolipoprotein C1
Apolipoprotein C1
Apolipoprotein C-I is a protein component of lipoproteins that in humans is encoded by the APOC1 gene.- Function :The protein encoded by this gene is a member of the apolipoprotein C family. This gene is expressed primarily in the liver, and it is activated when monocytes differentiate into...
and the Apolipoprotein C2. The APOE gene consists of four exons and three introns, totaling 3597 base pair
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...
s. In melanocytic cells
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
APOE gene expression may be regulated by MITF
Microphthalmia-associated transcription factor
Microphthalmia-associated transcription factor is a basic helix-loop-helix leucine zipper transcription factor involved in melanocyte and osteoclast development.-Clinical significance:...
.
ApoE is polymorphic
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
with three major isoforms, ApoE2, ApoE3, ApoE4, which translate into three alleles of the gene:
- Normal: ApoE-ε3
- Dysfunctional: ApoE-ε2 and ApoE-ε4
These allelic forms differ from each other only by amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
substitutions at positions 112 and 158..On Entrez SNP these are positions 130 and 176, rs429358 and rs7412 respectively; Entrez SNP positioning and positioning within Ensembl Genome Browser as 130 and 176 being those of the preprotein, intracellular proteolysis shifting these to positions 112 and 158. The E2 allele has a Cys at positions 112 and 158 in the receptor-binding region of ApoE. The E3 allele is Cys-112 and Arg-158. The ApoE E4 allele is Arg at both positions. These have physiological consequences:
- E2 is associated with the genetic disorderGenetic disorderA 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....
hyperlipoproteinemia type III and with both increased and decreased risk for atherosclerosisAtherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and type III hyperlipoproteinemia—94.4% of such patients are E2/E2, while only ∼2% of E2/E2 develop the disease. So other environmental and genetic factors are likely to be involved.
- E3 is found in approximately 64 percent of the population. It is considered the "neutral" Apo E genotype.
- E4 has been implicated in atherosclerosisAtherosclerosisAtherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
and Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, impaired cognitive function, and reduced neuriteNeuriteA neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
outgrowth.
ApoE is a target gene of the liver X receptor
Liver X receptor
The liver X receptor is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors are important regulators of cholesterol, fatty acid, and glucose homeostasis...
, a nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
member that plays a role in the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
regulation of cholesterol
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...
, fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
, and glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
.
| Estimated worldwide human allele frequencies of ApoE based upon over 200 world populations and 50,000 people (highly variable depending upon population)* | ||||
| Allele | ε2 | ε3 | ε4 | |
|---|---|---|---|---|
| Frequency | 0 - 37.5% | 8.5 - 98.0% | 0 - 49% | |
Alzheimer's Disease
The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's DiseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD) in a variety of ethnic groups. Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
(insoluble protein aggregates). Alzheimer's Disease is characterized by build-ups of aggregates of the peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
beta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. Some isoforms of ApoE are not as efficient as others at catalyzing these reactions. In particular, the isoform ApoE-ε4 is not very effective, resulting in increased vulnerability to Alzheimer's in individuals with that gene variation.
The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University
Duke University
Duke University is a private research university located in Durham, North Carolina, United States. Founded by Methodists and Quakers in the present day town of Trinity in 1838, the school moved to Durham in 1892. In 1924, tobacco industrialist James B...
Linkage studies were followed by association analysis confirming the role of the ApoE4 allele.
Although 40-65% of AD patients have at least one copy of the 4 allele, ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease. Yet those with two e4 alleles have up to 20 times the risk of developing AD. There is also evidence that the ApoE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer's disease and at earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer's disease. The genotype ApoE 2,3 is considered at less risk for Alzheimer's disease. Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk similar to the ApoE 3,3 genotype.
The connection between neuron failure in Alzheimer's disease and depleted myelin cholesterol (via ApoE deficiency) has also been described in Cholesterol Depletion and consequently is a known statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
therapy adverse drug reaction.