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Journal of Lipid Research, Vol. 44, 2257-2269, December 2003 Macrophage cholesterol efflux and the active domains of serum amyloid A 2.1
* Departments of Pathology, Kingston General Hospital, Kingston, Ontario K7L 3N6, Canada
1 To whom correspondence should be addressed. e-mail: kisilevsky{at}cliff.path.queensu.ca Serum amyloid A 2.1 (SAA2.1) suppresses ACAT and stimulates cholesteryl ester hydrolase (CEH) activities in cholesterol-laden macrophages, and in the presence of a cholesterol transporter and an extracellular acceptor, there is a marked increase in the rate of cholesterol export in culture and in vivo. 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. With liposomes containing individual peptides of SAA2.1, residues 120 inhibit ACAT activity, residues 74103 stimulate CEH activity, and each of residues 120 and 74103 promotes macrophage cholesterol efflux to HDL in culture media. In combination, these peptides exhibit a profound effect, so that 5570% of cholesterol is exported to media HDL in 24 h. The effect is also demonstrable in vivo. [3H]cholesterol-laden macrophages injected intravenously into mice were allowed to establish themselves for 24 h. Thereafter, the mice received a single intravenous injection of liposomes containing intact SAA1.1, SAA2.1, peptides composed of SAA2.1 residues 120, 2150, 5180, 74103, or SAA1.1 residues 120. Only liposomes containing intact SAA2.1 or its residues 120 or 74103 promoted 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.
Abbreviations: ApoA-I, apolipoprotein A-I; CEH, cholesteryl ester hydrolase; CQ, chloroquine; DIDS, 4,4-diisothiocyanotostilbene-2,2'-disulfonic acid; LPDS, lipoprotein-depleted serum; MCD, methyl-ß-cyclodextrin; RBC, red blood cell; SAA2.1, serum amyloid A 2.1 Supplementary key words acyl-CoA:cholesterol acyltransferase macrophages in vivo
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