Role of apolipoprotein A-IV and its polymorphisms for reverse cholesterol transport and coronary risk

Two-dimensional non-denaturing electrophoresis (2D-PAGGE) of normal plasma and subsequent anti-ape A-IV-immunoblotting differentiates LpA-IV1, LpA-IV2, and LpA-IV3. 2D-PAGGE of ape A-I deficient plasma and ape A-I-free plasma revealed that LpA-IV1 and LpA-IV2 do not contain apo A-I. The importance of LpA-IV1 and LpA-IV2 for uptake and esterification of cell-derived cholesterol was investigated by pulse-chase incubations of plasma with H-3 cholesterol-labeled fibroblasts and subsequent anti-apo A-I-immunosubtracting 2D-PAGGE. LpA-NI and LpA-IV2 take up and esterify cell-derived 3H cholesterol. LpA-IV1 and LpA-IV2 are thus ape A-I-free lipoproteins that contribute to reverse cholesterol transport. Next, we analyzed the impact of the apo A-IV(360:Gln/His)-polymorphism on risk factors and representation of coronary heart disease. Heterozygotes for ape A-IV(360:Gln/His) were approximately two years older than ape A-IV(360:Gln) homozygotes, when they experienced their first myocardial infarction (P < 0.05 in men). In both sexes, heterozygosity for ape A-IV (360:Gln/His) was associated with lower geometric mean concentrations of Lp(a). This polymorphism exerted opposite effects on serum concentrations of triglycerides, HDL cholesterol, LDL cholesterol, LpA-I, apo A-I, and ape B with more beneficial profiles in male ape A-TV(360:Gln/His) heterozygotes and female ape ATV(360:Gln) homozygotes. Apo A-IV(360:Gln/His) men also had higher concentrations of the fibrin split product D-dimer, female heterozygotes lower levels of the acute phase protein C-reactive protein. In conclusion, heterozygosity for apo A-TV(360:Gln/His) appears to decrease coronary risk. Possible reasons include beneficial effects of this polymorphism on lipid metabolism, fibrinolysis, and acute phase reaction.