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.

Abstract

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.

• Authors: Elda Favari, Monica Gomaraschi, Ilaria Zanotti, Franco Bernini, Miriam Lee-Rueckert, Petri T Kovanen, Cesare R Sirtori, Guido Franceschini, Laura Calabresi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 8 Pg. 5125-32 (Feb 23 2007) ISSN: 0021-9258 [Print] United States
• PMID: 17164237 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCA1 protein, human
• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters
• Apolipoprotein A-I
• High-Density Lipoproteins, Pre-beta
• Multiprotein Complexes
• apolipoprotein A-I Milano
• Cholesterol
• Chymases

Topics

• ATP Binding Cassette Transporter 1
• ATP-Binding Cassette Transporters (metabolism)
• Apolipoprotein A-I (chemistry, genetics, metabolism, pharmacology)
• Biological Transport (drug effects)
• Cell Line
• Cholesterol (metabolism)
• Chymases (chemistry)
• Coronary Disease (blood, genetics)
• Dimerization
• Female
• Fibroblasts (metabolism)
• High-Density Lipoproteins, Pre-beta (chemistry, metabolism, pharmacology)
• Humans
• Macrophages (metabolism)
• Male
• Multiprotein Complexes (chemistry, metabolism, pharmacology)