|, entrez:335, apo(a), apolipoprotein A1, Apolipoprotein A-I, HPALP2|
Apolipoprotein A1 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. The text in a 2014 report suggested that APOA1 mRNA is regulated by endogenously expressed antisense RNA.
The APOA1 gene is located on the 11th chromosome, with its specific location being 11q23-q24. The gene contains 4 exons. APOA1 encodes a 28.1 kDa protein that is composed of 243 amino acids; 21 peptides have been observed through mass spectrometry data.
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 cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. Apo A1 was also 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.
ApoA1 is often used as a biomarker for prediction of cardiovascular diseases. The ratio apoB-100/apoA1 (i.e. LDL & 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.
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 A1 helps to clear fats, including cholesterol, from white blood cells within artery walls, making the WBCs less likely to become fat overloaded, transform into foam cells, die and contribute to progressive atheroma. 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 apo A1 is present in roughly 0.3% of the Japanese population, but is found in 6% of those with low HDL cholesterol levels.
ApoA-1 Milano is a naturally occurring mutant of apo A1, found in a few families in Limone sul Garda, 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 apolipoproteins. 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 apo A1 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 apo A1 Milano dimers formulated into liposomes can reduce atheromas 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.
Novel haplotypes within apolipoprotein AI-CIII-AIV gene cluster
Lately,[when?] 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 apo A1 gene has been associated with the age at which patients presented with Alzheimer disease. Protection from Alzheimer's disease by apo A1 may rely on a synergistic interaction with alpha-tocopherol. Amyloid deposited in the knee following surgery consists largely of apo A1 secreted from chondrocytes (cartilage cells). A wide variety of amyloidosis symptoms are associated with rare Apo A1 mutants.
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
Apolipoprotein A1 has been shown to interact with:
Potential binding partners
Apolipoprotein A1 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
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
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- Overview of all the structural information available in the PDB for UniProt: Q00623 (Mouse Apolipoprotein A-I) at the PDBe-KB.