Macrophage cholesterol efflux and the active domains of serum amyloid A 2.1.
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 1-20 inhibit ACAT activity, residues 74-103 stimulate CEH activity, and each of residues 1-20 and 74-103 promotes macrophage cholesterol efflux to HDL in culture media. In combination, these peptides exhibit a profound effect, so that 55-70% 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 1-20, 21-50, 51-80, 74-103, or SAA1.1 residues 1-20. Only liposomes containing intact SAA2.1 or its residues 1-20 or 74-103 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.
Kisilevsky
Robert
R
Department of Pathology, Queen's Hospital, Kingston, Ontario K7L 3N6, Canada. kisilevsky@cliff.path.queensu.ca
Tam
Shui Pang
SP
D000818:Animals; D001053:Apolipoproteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D001692:Biological Transport; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D003505:Cyclodextrins / Q000494:pharmacology; D005260:Female; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017434:Protein Structure, Tertiary; D000685:Serum Amyloid A Protein / Q000737:chemistry* / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D047392:beta-Cyclodextrins
D001053:Apolipoproteins; D008076:Cholesterol, HDL; D003505:Cyclodextrins; D008081:Liposomes; D000685:Serum Amyloid A Protein; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002738:Chloroquine; D002784:Cholesterol; D000242:Cyclic AMP; D002785:Sterol O-Acyltransferase