Carriers of the apolipoprotein A-IMilano (A-IM) variant present with severe reductions of plasma HDL levels, not associated with premature coronary heart disease (CHD). Sera from 14 A-IM carriers and matched controls were compared for their ability to promote ABCA1-driven cholesterol efflux from J774 macrophages and human fibroblasts. When both cell types are stimulated to express ABCA1, the efflux of cholesterol through this pathway is greater with A-IM than control sera (3.4±1.0% versus 2.3±1.0% in macrophages; 5.2±2.4% versus 1.9±0.1% in fibroblasts). A-IM and control sera are instead equally effective in removing cholesterol from unstimulated cells and from fibroblasts not expressing ABCA1. The A-IM sera contain normal amounts of apoA-I-containing prebeta-HDL and varying concentrations of a unique small HDL particle containing a single molecule of the A-IM dimer; chymase treatment of serum degrades both particles and abolishes ABCA1-mediated cholesterol efflux. The serum content of chymase-sensitive HDL correlates strongly and significantly with ABCA1-mediated cholesterol efflux (r=0.542, p=0.004). The enhanced capacity of A-IM serum for ABCA1 cholesterol efflux is thus explained by the combined occurrence in serum of normal amounts of apoAI- containing prebeta-HDL, together with a unique protease-sensitive, small HDL particle containing the A-IM dimer, both effective in removing cell cholesterol via ABCA1.
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