A unique protease-sensitive high density lipoprotein particle containing the apolipoprotein A-I(Milano) dimer effectively promotes ATP-binding Cassette A1-mediated cell cholesterol efflux.
Carriers of the apolipoprotein A-I(Milano) (A-I(M)) variant present with severe reductions of plasma HDL levels, not associated with premature coronary heart disease (CHD). Sera from 14 A-I(M) 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-I(M) 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-I(M) and control sera are instead equally effective in removing cholesterol from unstimulated cells and from fibroblasts not expressing ABCA1. The A-I(M) 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-I(M) 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-I(M) serum for ABCA1 cholesterol efflux is thus explained by the combined occurrence in serum of normal amounts of apoA-I-containing prebeta-HDL, together with a unique protease-sensitive, small HDL particle containing the A-I(M) dimer, both effective in removing cell cholesterol via ABCA1.
Favari
Elda
E
Department of Pharmacological and Biological Sciences, and Applied Chemistries, University of Parma, Viale delle Scienze 27A, 43100 Parma, Italy.
Gomaraschi
Monica
M
Zanotti
Ilaria
I
Bernini
Franco
F
Lee-Rueckert
Miriam
M
Kovanen
Petri T
PT
Sirtori
Cesare R
CR
Franceschini
Guido
G
Calabresi
Laura
L
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D053818:Chymases / Q000737:chemistry; D003327:Coronary Disease / Q000097:blood / Q000235:genetics; D019281:Dimerization; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D053442:High-Density Lipoproteins, Pre-beta / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D053442:High-Density Lipoproteins, Pre-beta; D046912:Multiprotein Complexes; C080631:apolipoprotein A-I Milano; D002784:Cholesterol; D053818:Chymases