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J. Biol. Chem., Vol. 279, Issue 11, 9930-9936, March 12, 2004

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Depletion of Pre--high Density Lipoprotein by Human Chymase Impairs ATP-binding Cassette Transporter A1- but Not Scavenger Receptor Class B Type I-mediated Lipid Efflux to High Density Lipoprotein^*

Elda Favari, Miriam Lee¶, Laura Calabresi||, Guido Franceschini||, Francesca Zimetti, Franco Bernini, and Petri T. Kovanen**

From the Department of Pharmacological and Biological Sciences, and Applied Chemistry, University of Parma, Parma 43100, Italy, the Wihuri Research Institute, Helsinki 00140, Finland, the ^¶Department of Biochemistry, University of Havana, Havana H10400, Cuba, and the ^||Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milan, Milan 30126, Italy

The ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cellular unesterified cholesterol and phospholipid to lipid-poor apolipoprotein A-I. Chymase, a protease secreted by mast cells, selectively cleaves pre--migrating particles from high density lipoprotein (HDL)₃ and reduces the efflux of cholesterol from macrophages. To evaluate whether this effect is the result of reduction of ABCA1-dependent or -independent pathways of cholesterol efflux, in this study we examined the efflux of cholesterol to preparations of chymase-treated HDL₃ in two types of cell: 1) in J774 murine macrophages endogenously expressing low levels of scavenger receptor class B, type I (SR-BI), and high levels of ABCA1 upon treatment with cAMP; and 2) in Fu5AH rat hepatoma cells endogenously expressing high levels of the SR-BI and low levels of ABCA1. Treatment of HDL₃ with the human chymase resulted in rapid depletion of pre--HDL and a concomitant decrease in the efflux of cholesterol and phospholipid (2-fold and 3-fold, respectively) from the ABCA1-expressing J774 cells. In contrast, efflux of free cholesterol from Fu5AH to chymase-treated and to untreated HDL₃ was similar. Incubation of HDL₃ with phospholipid transfer protein led to an increase in pre--HDL contents as well as in ABCA1-mediated cholesterol efflux. A decreased cholesterol efflux to untreated HDL₃ but not to chymase-treated HDL₃ was observed in ABCA1-expressing J774 with probucol, an inhibitor of cholesterol efflux to lipid-poor apoA-I. Similar results were obtained using brefeldin and gliburide, two inhibitors of ABCA1-mediated efflux. These results indicate that chymase treatment of HDL₃ specifically impairs the ABCA1-dependent pathway without influencing either aqueous or SR-BI-facilitated diffusion and that this effect is caused by depletion of lipid-poor pre--migrating particles in HDL₃. Our results are compatible with the view that HDL₃ promotes ABCA1-mediated lipid efflux entirely through its lipid-poor fraction with pre- mobility.

Received for publication, November 14, 2003 , and in revised form, December 23, 2003.

^* This work was supported by grants from the Paavo Nurmi Foundation and the Sigrid Juselius Foundation (to M. L.) and by Grant QLGI-1999-01007 from the European Union (to P. T. K. 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.

^** To whom correspondence should be addressed: Wihuri Research Institute, Kalliolinnantie 4, Helsinki 00140, Finland. Tel.: 358-9-636-494; Fax: 358-9-637-476; E-mail: petri.kovanen{at}wri.fi.

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