Apolipoprotein AI (Apo-AI) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''APOA1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. As the major component of

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 ...

(HDL) particles, it has a specific role in

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

Structure

''APOA1'' is located on chromosome 11, with its specific location being 11q23-q24. The gene contains 4 exons. The encoded apolipoprotein AI, is a 28.1 kDa protein composed of 243 amino acids; 21 peptides have been observed through mass spectrometry data. Due to

alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

, there exists multiple transcript variants of ''APOA1'', including at least one which encodes a Apo-AI preprotein.

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''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85–92%), ...

s secreted from the intestinal

enterocyte Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase ...

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

low-density lipoprotein 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 density ...

(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. Apolipoprotein AI has also been isolated as a

prostacyclin Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator. When used as a drug, it is also known as epoprosteno ...

(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 ...

. Apo-AI is often used as a biomarker for prediction of cardiovascular diseases. The ratio apoB-100/apoA-I (i.e. LDL and larger particles vs. HDL particles), NMR measured 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. Apo-AI 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 is a solid-phase type of enzyme immunoassay (EIA) to detect the presence of ...

nephelometry A nephelometer or aerosol photometer is an instrument for measuring the concentration of suspension (chemistry), suspended particulates in a liquid or gas colloid. A nephelometer measures suspended particulates by employing a light beam (source b ...

Applications

Apo-AI can be used to create in vitro lipoprotein nanodiscs 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 complex (protective "fat removal" particles), Apo-AI helps to clear fats, including

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

, 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 accumulation of material in the tunica intima, inner layer of an arterial wall. The material consists of mostly macrophage, macrophage cells, or debris, containing lipids, calcium and a variabl ...

. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

. One of four mutants of Apo-AI 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 Apo-AI, found in a few families in Limone sul Garda, Italy, and, by genetic and 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 Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

bridge, causing it to exist as a

homodimer In biochemistry, a protein dimer is a macromolecular complex or protein multimer, multimer formed by two protein monomers, or single proteins, which are usually Non-covalent interaction, non-covalently bound. Many macromolecules, such as proteins ...

or as a

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

with Apo-AII. However, the enhanced cardioprotective activity of this mutant (which likely depends on fat & cholesterol efflux) cannot easily be replicated by other cysteine mutants. Recombinant Apo-AI Milano dimers formulated into liposomes can reduce

s in animal models by up to 30%. Apo-AI 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

A study from 2008 describes two novel susceptibility haplotypes, P2-S2-X1 and P1-S2-X1, 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 type 2 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 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 typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

deposited in the knee following surgery consists largely of Apo-AI secreted from

chondrocytes Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...

(

cartilage Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

cells). A wide variety of

symptoms are associated with rare ''APOA1'' mutants. Apo-AI binds to

lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...

endotoxin Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...

, 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 Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

patients' CSF, brain and peripheral tissues.

Epistatic impact of Apo-AI

Apolipoprotein AI and ApoE interact epistatically to modulate triglyceride levels in coronary heart disease patients. Individually, neither Apo-AI nor ApoE 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-AI activity

In a study from 2005 it was reported, that Apo-AI production is decreased by

calcitriol Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the exp ...

. It was concluded, that this regulation happens on transcription level: calcitriol alters yet unknown coactivators or corepressors, resulting in repression of ''APOA1'' promoter activity. Simultaneously, Apo-AI production was increased by vitamin D antagonist, ZK-191784. Exercise or

statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

treatment may cause an increase in HDL-C levels by inducing Apo-AI production, but this depends on the G/A promoter polymorphism.

Interactions

Apolipoprotein A1 has been shown to interact with: * ABCA1 * GPLD1 * PLTP

Potential binding partners

Apolipoprotein AI binding precursor, a relative of APOA-1 abbreviated APOA1BP, 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

References

External links

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