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Papers In Press, published online ahead of print September 1, 2003
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Pathology Dept., Queen's University, Kingston, Ontario K7L 3N6
Corresponding Author: kisilevsky{at}cliff.path.queensu.ca
Previously we showed that SAA2.1 suppresses ACAT and stimulates CEH activities in cholesterol-laden macrophages. This shifts cholesterol into its unesterified form and in the presence of a cholesterol transporter and an extracellular acceptor there is a marked increase in its rate of export in culture and in vivo. We now show that the stimulation of CEH activity by SAA2.1 is not affected by chloroquine suggesting that it operates on neutral CEH rather than the lysosomal form. Studies in culture show that promotion of cholesterol efflux by SAA 2.1 is increased by cAMP, but not by cyclodextrin. The latter increases the initial rate of efflux in the presence of SAA2.1 and cAMP. With liposomes containing individual peptides that span the entire length of SAA2.1 residues 1-20 inhibits ACAT activity, residues 74-103 stimulates CEH activity, and each of residues 1-20 and 74-103 promotes macrophage cholesterol efflux to HDL in the culture medium. In combination, these peptides exhibit a profound effect so that 55-70% of cholesterol, by mass or isotope, in cholesterol-laden cells is exported to media HDL in 24 h. The effect of these peptides are also demonstrated in vivo. 3[H]-Cholesterol-laden macrophages injected IV were allowed to establish themselves in vivo for 24 h. Thereafter the mice received a single IV injection of liposomes containing either intact SAA1.1, or 2.1, or peptides composed of SAA2.1 residues 1-20, 21-50, 51-80, 74-103, or SAA1.1 residues 1-20. Only liposomes containing intact SAA 2.1, its residues 1-20, or 74-103, the ACAT inhibiting and CEH enhancing domains of SAA2.1, respectively, promote the efflux of cholesterol in vivo. A single injection of each of the active peptides is effective in promoting cholesterol efflux in vivo for at least 4 days. These data define the active domains of SAA2.1 vis a vis macrophage ACAT, CEH and cholesterol efflux activities.
Revised on July 24, 2003
Accepted on August 21, 2003
Macrophage cholesterol efflux and the active domains of serum amyloid A2.1
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