Apolipoprotein A1

Apolipoprotein A1 is a is_associated_with::protein that in humans is encoded by the APOA1 is_associated_with::gene. It has a specific role in is_associated_with::lipid metabolism. Recent report suggest that APOA1 mRNA is regulated by endogenously expressed antisense RNA.

Apolipoprotein A1 is the major protein component of is_associated_with::high density lipoprotein (HDL) in plasma. Chylomicrons secreted from the intestinal enterocyte also contain apo A1, but it is quickly transferred to HDL in the bloodstream. The protein promotes fat efflux, including is_associated_with::cholesterol, from tissues to the liver for excretion. It is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma is_associated_with::cholesteryl esters. Apo A1 was also isolated as a is_associated_with::prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect. Defects in the gene encoding it are associated with HDL deficiencies, including is_associated_with::Tangier disease, and with systemic non-neuropathic is_associated_with::amyloidosis. ApoA1 is often used as a biomarker for prediction of cardiovascular diseases and the ratio apoB- 100/apoA1 has been reported as a stronger predictor for the risk of myocardial infarction than any other lipid measurement. ApoA1 is routinely measured using immunoassays such as is_associated_with::ELISA or is_associated_with::nephelometry.

Structure
The APOA1 gene is located on the 11th chromosome, with its specific location being 11q23-q24. The gene contains 4 exons. APOA1 encodes a 45.4 kDa protein that is composed of 396 amino acids; 21 peptides have been observed through mass spectrometry data.

Activity associated with high HDL-C and protection from heart disease
As a major component of the is_associated_with::high-density lipoprotein complex (protective "fat removal" particles), apo A1 helps to clear fats, including is_associated_with::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 is_associated_with::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.

is_associated_with::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 in the 14th century. Described in 1980, it was the first known molecular abnormality of is_associated_with::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 is_associated_with::cysteine bridge, causing it to exist as a is_associated_with::homodimer or as a is_associated_with::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 is_associated_with::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.

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 apo A1 gene has been associated with the age at which patients presented with is_associated_with::Alzheimer disease. Protection from Alzheimer's disease by apo A1 may rely on a synergistic interaction with is_associated_with::alpha-tocopherol. is_associated_with::Amyloid deposited in the knee following surgery consists largely of apo A1 secreted from is_associated_with::chondrocytes (is_associated_with::cartilage cells). A wide variety of is_associated_with::amyloidosis symptoms are associated with rare Apo A1 mutants.

Apo A-I binds to is_associated_with::lipopolysaccharide or is_associated_with::endotoxin, and has a major role in the anti-endotoxin function of HDL.

In one study, a decrease in apo A1 levels was detected in is_associated_with::schizophrenia patients' CSF, 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 however, 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 is_associated_with::calcitriol, and increased by a drug that antagonizes it.

Exercise or is_associated_with::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:
 * is_associated_with::ABCA1,
 * is_associated_with::GPLD1 and
 * is_associated_with::PLTP.

Potential binding partners
Apolipoprotein A1 binding precursor, a relative of APOA-1 abbreviated is_associated_with::APOA1BP, has a predicted biochemical interaction with Carbohydrate Kinase Domain Containing Protein. The relationship between these two proteins is substantiated by is_associated_with::cooccurance across genomes and is_associated_with::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.