Apolipoprotein A-I, also known as APOA1, is a human gene.

The protein encoded by this gene is an apolipoprotein. It is the major protein component of high density lipoprotein (HDL) in plasma. The protein promotes cholesterol efflux from tissues to the liver for excretion. It is a cofactor for lecithin cholesterolacyltransferase (LCAT) which is responsible for the formation of most plasma cholesteryl esters. ApoA-I was also isolated as a prostacyclin (PGI2) stabilizing factor, and thus may have an anticlotting effect.^[1] Defects in the gene encoding it are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis.^[2]

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

As a major component of the high density lipoprotein complex ("good cholesterol"), ApoA-I helps to clear cholesterol from arteries. Five of nine men found to carry a mutation (E164X) who were at least 35 years of age had developed premature coronary artery disease.^[3] One of four mutants of ApoA-I is present in roughly 0.3% of the Japanese population, but is found 6% of those with low HDL cholesterol levels.

ApoA-I Milano is a naturally occurring mutant of ApoA-I, found in a family descended from a single couple of the 18th century. Described in 1980, it was the first known molecular abnormality of apolipoproteins.^[4] Paradoxically, carriers of this mutation have very low HDL cholesterol levels, but no increase in the risk of heart disease. Biochemically, ApoA-I contains an extra cysteine bridge, causing it to exist as a homodimer or as a heterodimer with ApoA-II. However, the enhanced cardioprotective activity of this mutant (which likely depends on cholesterol efflux) cannot easily be replicated by other cysteine mutants.^[5]

Recombinant Apo-I Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.^[6] ApoA-I Milano has also been shown in small clinical trials to have a statistically significant effect in reducing (reversing) plaque build-up on arterial walls.^[7][8]

In human trials the reversal of plaque build-up was measured over the course of five weeks.^[7][9]

APP018 (formerly D-4F), an 18-amino acid peptide (Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2^[10][11] (using D-amino acids) that can be taken orally, was developed by Bruin Pharmaceuticals (a little-known company founded by Dr. Alan Fogelman, named after the UCLA Bruins^[12][13] and sold to Novartis for $200 million USD. The peptide and close variations thereof such as D-5F have been shown to elevate HDL-C and reduce atherosclerotic build-up in early animal data. The peptide has been tested with a variety of modifications, formulated with an excipient such as poly(lactide-co-glycolide) (PLG), and formed into ProLease drug-polymer microspheres.^[14] If all continues to go well it is expected to reach the pharmacy shelf around 2013.^[15]

• 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 chromosme 11q23, who confer approximately threefold higher risk of coronary heart disease in normal^[16] as well as non-insulin diabetes mellitus.^[17]

Role in other diseases

A G/A polymorphism in the promoter of the ApoA-I gene has been associated with the age at which patients presented with Alzheimer disease.^[18] Protection from Alzheimer disease by ApoA1 may rely on a synergistic interaction with alpha-tocopherol.^[19] Apolipoprotein A-I and APOE interact epistatically to modulate triglyceride levels in Coronary Heart Disease patients.^[20] Amyloid deposited in the knee following surgery consists largely of ApoA-I secreted from chondrocytes (cartilage cells).^[21] A wide variety of amyloidosis symptoms are associated with rare ApoA-I mutants.

ApoA-I binds to lipopolysaccharide or endotoxin, and has a major role in the anti-endotoxin function of HDL.^[22]

In one study, a decrease in ApoA1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.^[23]

Factors affecting ApoA-I activity

ApoA-I production is decreased by Vitamin D, and increased by a drug that antagonizes it.^[24]

Exercise or statin treatment may cause an increase in HDL-C levels by inducing ApoA-I production, but this depends on the G/A promoter polymorphism.^[25]

References

External links

pl:Apolipoproteina A-I ru:?????????????? A1 fi:APO A-1 Milano