载脂蛋白A1

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.[10]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.[11]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.[12]

Recombinant apo A1 Milano dimers formulated into liposomes can reduce atheromas in animal models by up to 30%.[13]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.[14][15]

In human trials the reversal of plaque build-up was measured over the course of five weeks.[14][16]

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[17]as well as in the patients having non-insulin diabetes mellitus.[18]

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.[19]Protection from Alzheimer's disease by apo A1 may rely on a synergistic interaction with alpha-tocopherol.[20] Amyloid deposited in the knee following surgery consists largely of apo A1 secreted from chondrocytes (cartilage cells).[21]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.[22]

In one study, a decrease in apo A1 levels was detected in schizophrenia patients' CSF, brain and peripheral tissues.[23]

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). [24]

Factors affecting apo A1 activity

Apo A1 production is decreased by calcitriol, and increased by a drug that antagonizes it.[25]

Exercise or statin treatment may cause an increase in HDL-C levels by inducing apo A1 production, but this depends on the G/A promoter polymorphism.[26]

交互作用

載脂蛋白A1可與下列蛋白產生交互作用：

• ABCA1[27]
• GPLD1[28]and
• PLTP[29]