Apolipoprotein A1 is a protein that in humans is encoded by the APOA1 gene. It
has a specific role in lipid metabolism. Recent report suggest that APOA1 mRNA is
regulated by endogenously expressed antisense RNA.
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.
Function Apolipoprotein A1 is the major protein
component of high density lipoprotein 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 cholesterol, from
tissues to the liver for excretion. It is a cofactor for lecithin
cholesterolacyltransferase which is responsible for the formation of most
plasma cholesteryl esters. Apo A1 was also isolated as a prostacyclin
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 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 ELISA or nephelometry.
Clinical significance = Activity associated with high HDL-C
and protection from heart disease = As a major component of the high-density
lipoprotein complex, 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 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 in the 14th century.
Described in 1980, it was the first known molecular abnormality of
apolipoproteins. Paradoxically, carriers of this mutation have very low HDL-C
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.
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 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 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
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. A wide variety of amyloidosis symptoms are associated with
rare Apo A1 mutants. Apo A-I binds to lipopolysaccharide or
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 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 levels, but pairwise epistasis explored their significant
synergistic contributions with raised TG levels (P