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J. Biol. Chem., Vol. 282, Issue 8, 5125-5132, February 23, 2007

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A Unique Protease-sensitive High Density Lipoprotein Particle Containing the Apolipoprotein A-IMilano Dimer Effectively Promotes ATP-binding Cassette A1-mediated Cell Cholesterol Efflux^*

Elda Favari, Monica Gomaraschi, Ilaria Zanotti, Franco Bernini, Miriam Lee-Rueckert^¶, Petri T. Kovanen^¶, Cesare R. Sirtori, Guido Franceschini¹, and Laura Calabresi

From the Department of Pharmacological and Biological Sciences, and Applied Chemistries, University of Parma, Viale delle Scienze 27A, 43100 Parma, Italy, the Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milano, Via Balzaretti 9, 20133 Milano, Italy, and the ^¶Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland

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 pre-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 pre-HDL, together with a unique protease-sensitive, small HDL particle containing the A-I_M dimer, both effective in removing cell cholesterol via ABCA1.

Received for publication, October 3, 2006 , and in revised form, December 5, 2006.

^* This work was supported by grants from the Italian Ministry of University and Research (PRIN 2005 to G. F. and F. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Center E. Grossi Paoletti, Dept. of Pharmacological Sciences, Via Balzaretti 9, 20133 Milano, Italy. Tel.: 39-0250319911; Fax: 39-0250319900; E-mail: Guido.Franceschini{at}unimi.it.

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