Abstract
It has been suggested that ABCA1 interacts preferentially with lipid-poor apolipoprotein A-I (apoA-I). Here, we show that treatment of plasma with dimyristoyl phosphatidylcholine (DMPC) multilamellar vesicles generates prebeta(1)-apoA-I-containing lipoproteins (LpA-I)-like particles similar to those of native plasma. Isolated prebeta(1)-LpA-I-like particles inhibited the binding of (125)I-apoA-I to ABCA1 more efficiently than HDL(3) (IC(50) = 2.20 +/- 0.35 vs. 37.60 +/- 4.78 microg/ml). We next investigated the ability of DMPC-treated plasma to promote phospholipid and unesterified (free) cholesterol efflux from J774 macrophages stimulated or not with cAMP. At 2 mg DMPC/ml plasma, both phospholipid and free cholesterol efflux were increased ( approximately 50% and 40%, respectively) in cAMP-stimulated cells compared with unstimulated cells. Similarly, both phospholipid and free cholesterol efflux to either isolated native prebeta(1)-LpA-I and prebeta(1)-LpA-I-like particles were increased significantly in stimulated cells. Furthermore, glyburide significantly inhibited phospholipid and free cholesterol efflux to DMPC-treated plasma. Removal of apoA-I-containing lipoproteins from normolipidemic plasma drastically reduced free cholesterol efflux mediated by DMPC-treated plasma. Finally, treatment of Tangier disease plasma with DMPC affected the amount of neither prebeta(1)-LpA-I nor free cholesterol efflux. These results indicate that DMPC enrichment of normal plasma resulted in the redistribution of apoA-I from alpha-HDL to prebeta-HDL, allowing for more efficient ABCA1-mediated cellular lipid release. Increasing the plasma prebeta(1)-LpA-I level by either pharmacological agents or direct infusions might prevent foam cell formation and reduce atherosclerotic vascular disease.
Highlights
It has been suggested that ABCA1 interacts preferentially with lipid-poor apolipoprotein A-I
Plasma samples from three normolipidemic subjects (Table 1) treated or not with dimyristoyl phosphatidylcholine (DMPC)-multilamellar vesicle (MLV) (2 mg/ml plasma) were separated by 2D-PAGGE, and different HDL subpopulations were quantified by densitometric scanning of radiographic films used to detect the presence of apolipoprotein A-I (apoA-I) associated with HDL subfractions
We demonstrate that incubation of plasma with either POPCMLV or bovine brain sphingomyelin (BBSM)-MLV did not significantly affect plasma pre1-LpA-I levels
Summary
It has been suggested that ABCA1 interacts preferentially with lipid-poor apolipoprotein A-I (apoA-I). Treatment of Tangier disease plasma with DMPC affected the amount of neither pre1-LpA-I nor free cholesterol efflux These results indicate that DMPC enrichment of normal plasma resulted in the redistribution of apoA-I from ␣-HDL to pre-HDL, allowing for more efficient ABCA1-mediated cellular lipid release. The importance of ABCA1 in the lipidation of apolipoprotein A-I (apoA-I) is highlighted by the finding that Ͼ50 mutations in the ABCA1 gene have been associated with a variety of clinically distinct HDL deficiency diseases, including Tangier disease (TD) and familial HDL deficiency [6, 7] These patients are characterized by extremely low HDL-cholesterol levels, caused by defective transport of cellular cholesterol and phospholipids to the extracellular space, leading to hypercatabolism of lipidpoor nascent HDL particles [8].
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