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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 Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
.


Structure

''APOA1'' is located on
chromosome 11 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
, with its specific location being 11q23-q24. The gene contains 4 exons. The encoded apolipoprotein A-I, is a 28.1 kDa protein composed of 243 amino acids; 21 peptides have been observed through mass spectrometry data.


Function

Apolipoprotein AI is the major protein component of high density lipoprotein (HDL) particles in plasma.
Chylomicron 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 (8 ...
s secreted from the intestinal enterocyte also contain apo-AI, but it is quickly transferred to HDL in the bloodstream. The protein, as a component of HDL particles, enables efflux of fat molecules by accepting fats from within cells (including macrophages within the walls of arteries which have become overloaded with ingested fats from oxidized LDL particles) for transport (in the water outside cells) elsewhere, including back to LDL particles or to the liver for excretion. It is a cofactor for lecithin—cholesterol acyltransferase (LCAT) which is responsible for the formation of most plasma
cholesteryl esters 300px, Cholesterol oleate, a member of the cholesteryl ester family Cholesteryl ester, a dietary lipid, is an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cho ...
. Apolipoprotein AI has also been isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect. Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic
amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weigh ...
. ApoA-I is often used as a biomarker for prediction of cardiovascular diseases. The ratio apoB-100/apoA-I (i.e. LDL & larger particles vs. HDL particles), NMR measured lipoprotein ( low density lipoprotein (LDL)/(HDL) particle ratios even more so, has always had a stronger correlation with myocardial infarction event rates than older methods of measuring lipid transport in the water outside cells. ApoA-I is routinely measured using immunoassays such as
ELISA The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presenc ...
or nephelometry.


Applications

ApoA-I can be used to create in vitro lipoprotein
nanodisc A nanodisc is a synthetic model membrane system which assists in the study of membrane proteins. Nanodiscs are discoidal proteins in which a lipid bilayer is surrounded by molecules that are amphipathic molecules including proteins, peptides, and ...
s for cell-free membrane expression systems.


Clinical significance


Activity associated with high HDL-C and protection from heart disease

As a major component of the
high-density lipoprotein High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...
complex (protective "fat removal" particles), apoA-I helps to clear fats, including cholesterol, from white blood cells within artery walls, making the white blood cells (WBCs) less likely to become fat overloaded, transform into foam cells, die and contribute to progressive
atheroma An atheroma, or atheromatous plaque, is an abnormal and reversible accumulation of material in the inner layer of an arterial wall. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount o ...
. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease. One of four mutants of apoA-I is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels. ApoA-I Milano is a naturally occurring mutant of apoA-I, found in a few families in
Limone sul Garda Limone sul Garda ( Gardesano: ) is a town and ''comune'' in the province of Brescia, in Lombardy (northern Italy), at the western bank of Lake Garda. History Despite the presence of famous cultivations of lemons (the meaning of in Italian), the ...
, Italy, and, by genetic + church record family tree detective work, traced to a single individual, Giovanni Pomarelli, in the 18th century. Described in 1980, it was the first known molecular abnormality of
apolipoprotein Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. The lipid components of lipoprotei ...
s. Paradoxically, carriers of this mutation have very low HDL-C (HDL-Cholesterol) levels, but no increase in the risk of heart disease, often living to age 100 or older. This unusual observation was what lead Italian investigators to track down what was going on and lead to the discovery of apoA-I Milano (the city, Milano, ~160 km away, in which the researcher's lab was located). Biochemically, apo A1 contains an extra cysteine bridge, causing it to exist as a homodimer or as a heterodimer with apo A-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants. Recombinant ApoA-1 Milano dimers formulated into liposomes can reduce
atheroma An atheroma, or atheromatous plaque, is an abnormal and reversible accumulation of material in the inner layer of an arterial wall. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable amount o ...
s in animal models by up to 30%. Apo A1 Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls. In human trials the reversal of plaque build-up was measured over the course of five weeks.


Novel haplotypes within apolipoprotein AI-CIII-AIV gene cluster

Lately, two novel susceptibility haplotypes i.e. P2-S2-X1 and P1-S2-X1 have been discovered in ApoAI-CIII-AIV gene cluster on chromosome 11q23, which confer approximately threefold higher risk of coronary heart disease in normal as well as in the patients having non-insulin diabetes mellitus.


Role in other diseases

A G/A polymorphism in the promoter of the ''APOA1'' gene has been associated with the age at which
Alzheimer disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
is presented. Protection from Alzheimer's disease by apo-AI may rely on a synergistic interaction with alpha-tocopherol.
Amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the hum ...
deposited in the knee following surgery consists largely of apo-AI secreted from
chondrocytes Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
(
cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...
cells). A wide variety of
amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weigh ...
symptoms are associated with rare ''APOA1'' mutants. Apo-AI binds to
lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer me ...
or endotoxin, and has a major role in the anti-endotoxin function of HDL. In one study, a decrease in Apo-AI levels was detected in schizophrenia patients'
CSF CSF may refer to: Biology and medicine * Cerebrospinal fluid, clear colorless bodily fluid found in the brain and spine * Colony-stimulating factor, secreted glycoproteins * Cancer slope factor, estimate the risk of cancer * Classical swine fev ...
, brain and peripheral tissues.


Epistatic impact of apo A1

Apolipoprotein A1 and APOE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither apo A1 nor apo E was found to be associated with triglyceride (TG) levels, but pairwise epistasis (additive x additive model) explored their significant synergistic contributions with raised TG levels (P<0.01).


Factors affecting apo A1 activity

Apo-A1 production is decreased by
calcitriol Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the ...
, and increased by a drug that antagonizes it. Exercise or statin treatment may cause an increase in HDL-C levels by inducing apo A1 production, but this depends on the G/A promoter polymorphism.


Interactions

Apolipoprotein A1 has been shown to interact with: *
ABCA1 ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), also known as the ''cholesterol efflux regulatory protein'' (CERP) is a protein which in humans is encoded by the ''ABCA1'' gene. This transporter is a major ...
* GPLD1 * PLTP


Potential binding partners

Apolipoprotein A1 binding precursor, a relative of APOA-1 abbreviated
APOA1BP Apolipoprotein A-I-binding protein also known as APOA1BP is a protein that in humans is encoded by the ''APOA1BP'' gene. Function APOA1BP binds to APOA1, APOA2, and high-density lipoprotein High-density lipoprotein (HDL) is one of the five ...
, has a predicted biochemical interaction with Carbohydrate Kinase Domain Containing Protein. The relationship between these two proteins is substantiated by cooccurance across genomes and coexpression. The ortholog of CARKD in ''E. coli'' contains a domain not present in any eukaryotic ortholog. This domain has a high sequence identity to APOA1BP. CARKD is a protein of unknown function, and the biochemical basis for this interaction is unknown.


Interactive pathway map


See also

*
Apolipoprotein B 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), IDL, and LDL particles (LDL—commonly known as "bad cholesterol" when in ref ...
*
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 ...
*
ApoA-1 Milano Apolipoprotein A-1 Milano (also ETC-216, now MDCO-216) is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated wit ...


References


External links

*
Applied Research on Apolipoprotein-A1
* * * {{Lipoproteins Apolipoproteins zh:载脂蛋白