Serum amyloid A promotes cholesterol efflux mediated by scavenger receptor B-I.
Serum amyloid A (SAA) is an acute phase protein whose expression is markedly up-regulated during inflammation and infection. The physiological function of SAA is unclear. In this study, we reported that SAA promotes cellular cholesterol efflux mediated by scavenger receptor B-I (SR-BI). In Chinese hamster ovary cells, SAA promoted cellular cholesterol efflux in an SR-BI-dependent manner, whereas apoA-I did not. Similarly, SAA, but not apoA-I, promoted cholesterol efflux from HepG2 cells in an SR-BI-dependent manner as shown by using the SR-BI inhibitor BLT-1. When SAA was overexpressed in HepG2 cells using adenovirus-mediated gene transfer, the endogenously expressed SAA promoted SR-BI-dependent efflux. To assess the effect of SAA on SR-BI-mediated efflux to high density lipoprotein (HDL), we compared normal HDL, acute phase HDL (AP-HDL, prepared from mice injected with lipopolysaccharide), and AdSAA-HDL (HDL prepared from mice overexpressing SAA). Both AP-HDL and AdSAA-HDL promoted 2-fold greater cholesterol efflux than normal HDL. Lipid-free SAA was shown to also stimulate ABCA1-dependent cholesterol efflux in fibroblasts, in line with an earlier report (Stonik, J. A., Remaley, A. T., Demosky, S. J., Neufeld, E. B., Bocharov, A., and Brewer, H. B. (2004) Biochem. Biophys. Res. Commun. 321, 936-941). When added to cells together, SAA and HDL exerted a synergistic effect in promoting ABCA1-dependent efflux, suggesting that SAA may remodel HDL in a manner that releases apoA-I or other efficient ABCA1 ligands from HDL. SAA also facilitated efflux by a process that was independent of SR-BI and ABCA1. We conclude that the acute phase protein SAA plays an important role in HDL cholesterol metabolism by promoting cellular cholesterol efflux through a number of different efflux pathways.
van der Westhuyzen
Deneys R
DR
Department of Internal Medicine, Graduate Center for Nutrition Sciences, University of Kentucky Medical Center, Lexington, Kentucky 40536-0200, USA. dvwest1@uky.edu
Cai
Lei
L
de Beer
Maria C
MC
de Beer
Frederick C
FC
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D006801:Humans; D007249:Inflammation; D008024:Ligands; D008075:Lipoproteins, HDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018102:Receptors, Leukotriene B4 / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism / Q000502:physiology*; D000685:Serum Amyloid A Protein / Q000502:physiology*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C513240:LTB4R protein, human; D008024:Ligands; D008075:Lipoproteins, HDL; C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D018048:Receptors, Purinergic P2; D011994:Recombinant Proteins; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D000685:Serum Amyloid A Protein; D002784:Cholesterol