Studies suggest that inflammation impairs reverse cholesterol transport (RCT). We investigated whether serum amyloid A (SAA) contributes to this impairment using an established macrophage-to-feces RCT model. Wild-type (WT) mice and mice deficient in SAA1.1 and SAA2.1 (SAAKO) were injected intraperitoneally with 3H-cholesterol-labeled J774 macrophages 4？hr after administration of LPS or buffered saline. 3H-cholesterol in plasma 4？hr after macrophage injection was significantly reduced in both WT and SAAKO mice injected with LPS, but this was not associated with a reduced capacity of serum from LPS-injected mice to promote macrophage cholesterol efflux in vitro. Hepatic accumulation of 3H-cholesterol was unaltered in either WT or SAAKO mice by LPS treatment. Radioactivity present in bile and feces of LPS-injected WT mice 24？hr after macrophage injection was reduced by 36%？？ and 80%？？ , respectively. In contrast, in SAAKO mice, LPS did not significantly reduce macrophage-derived 3H-cholesterol in bile, and fecal excretion was reduced by only 45%？？ . Injection of cholesterol-loaded allogeneic J774 cells, but not syngeneic bone-marrow-derived macrophages, transiently induced SAA in C57BL/6 mice. Our study confirms reports that acute inflammation impairs steps in the RCT pathway and establishes that SAA plays only a minor role in this impairment. 1. Introduction Epidemiological studies have identified a strong inverse relationship between the risk of cardiovascular disease and plasma HDL levels [1]. One of the primary antiatherogenic properties of HDL is thought to be its role in reverse cholesterol transport (RCT), a process whereby excess cholesterol is removed from peripheral tissues, including lipid-loaded macrophages in the vessel wall, and transported to the liver for excretion in the bile and feces [2]. Accelerated atherosclerosis has been associated with inflammatory diseases such as rheumatoid arthritis [3], and inflammatory biomarkers are increasingly used as predictors of cardiovascular disease progression [4, 5]. Inflammation gives rise to numerous metabolic and structural changes in lipoproteins, particularly HDL, which may impact the ability of HDL to mediate RCT [6, 7]. Inflammatory HDL undergoes structural and compositional changes, most notably an increase in its serum amyloid A (SAA) content, to the extent that SAA can become the major apolipoprotein of HDL [8]. SAA is a major hepatic acute phase reactant and can account for as much as 2.5% of the protein produced in the liver during severe inflammation [9]. During the acute phase, plasma
References
[1]
G. Assmann and A. M. Gotto Jr., “HDL cholesterol and protective factors in atherosclerosis,” Circulation, vol. 109, no. 23, pp. III8–III14, 2004.
[2]
M. Cuchel and D. J. Rader, “Macrophage reverse cholesterol transport: key to the regression of atherosclerosis?” Circulation, vol. 113, no. 21, pp. 2548–2555, 2006.
[3]
C. P. Chung, A. Oeser, P. Raggi et al., “Increased coronary-artery atherosclerosis in rheumatoid arthritis: relationship to disease duration and cardiovascular risk factors,” Arthritis and Rheumatism, vol. 52, no. 10, pp. 3045–3053, 2005.
[4]
S. Tsimikas, J. T. Willerson, and P. M. Ridker, “C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients,” Journal of the American College of Cardiology, vol. 47, no. 8, pp. C19–C31, 2006.
[5]
D. J. Rader, “Inflammatory markers of coronary risk,” The New England Journal of Medicine, vol. 343, no. 16, pp. 1179–1182, 2000.
[6]
W. Khovidhunkit, M. S. Kim, R. A. Memon et al., “Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host,” Journal of Lipid Research, vol. 45, no. 7, pp. 1169–1196, 2004.
[7]
D. R. Van Der Westhuyzen, F. C. De Beer, and N. R. Webb, “HDL cholesterol transport during inflammation,” Current Opinion in Lipidology, vol. 18, no. 2, pp. 147–151, 2007.
[8]
G. A. Coetzee, A. F. Strachan, and D. R. Van Der Westhuyzen, “Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition,” Journal of Biological Chemistry, vol. 261, no. 21, pp. 9644–9651, 1986.
[9]
C. M. Uhlar and A. S. Whitehead, “Serum amyloid A, the major vertebrate acute-phase reactant,” European Journal of Biochemistry, vol. 265, no. 2, pp. 501–523, 1999.
[10]
J. Sipe, “Part 2: Revised nomenclature for serum amyloid a (SAA),” Amyloid, vol. 6, no. 1, pp. 67–70, 1999.
[11]
A. S. Whitehead, M. C. De Beer, D. M. Steel et al., “Identification of novel members of the serum amyloid A protein superfamily as constitutive apolipoproteins of high density lipoprotein,” Journal of Biological Chemistry, vol. 267, no. 6, pp. 3862–3867, 1992.
[12]
T. Chiba, C. Y. Han, T. Valsar et al., “Serum amyloid A3 does not contribute to circulating SAA levels,” Journal of Lipid Research, vol. 50, no. 7, pp. 1353–1362, 2009.
[13]
M. C. De Beer, N. R. Webb, J. M. Wroblewski et al., “Impact of serum amyloid A on high density lipoprotein composition and levels,” Journal of Lipid Research, vol. 51, no. 11, pp. 3117–3125, 2010.
[14]
F. C. McGillicuddy, M. de la Llera Moya, C. C. Hinkle, et al., “Inflammation impairs reverse cholesterol transport in vivo,” Circulation, vol. 119, no. 8, pp. 1135–1145, 2009.
[15]
W. Annema, N. Nijstad, M. T？lle et al., “Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2,” Journal of Lipid Research, vol. 51, no. 4, pp. 743–754, 2010.
[16]
P. Malik, S. Z. Berisha, J. Santore, C. Agatisa-Boyle, G. Brubaker, and J. D. Smith, “Zymosan-mediated inflammation impairs in vivo reverse cholesterol transport,” Journal of Lipid Research, vol. 52, no. 5, pp. 951–957, 2011.
[17]
S. Yona, S. E. M. Heinsbroek, L. Peiser, S. Gordon, M. Perretti, and R. J. Flower, “Impaired phagocytic mechanism in annexin 1 null macrophages,” British Journal of Pharmacology, vol. 148, no. 4, pp. 469–477, 2006.
[18]
Z. Zhao, M. C. De Beer, L. Cai et al., “Low-density lipoprotein from apolipoprotein E-deficient mice induces macrophage lipid accumulation in a CD36 and scavenger receptor class A-dependent manner,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 1, pp. 168–173, 2005.
[19]
Y. Zhang, I. Zanotti, M. P. Reilly, J. M. Glick, G. H. Rothblat, and D. J. Rader, “Overexpression of apolipoprotein A-I promotes reverse transport of cholesterol from macrophages to feces in vivo,” Circulation, vol. 108, no. 6, pp. 661–663, 2003.
[20]
B. F. Asztalos, M. De La Llera-Moya, G. E. Dallal, K. V. Horvath, E. J. Schaefer, and G. H. Rothblat, “Differential effects of HDL subpopulations on cellular ABCA1- and SR-BI-mediated cholesterol efflux,” Journal of Lipid Research, vol. 46, no. 10, pp. 2246–2253, 2005.
[21]
G. A. Francis, R. H. Knopp, and J. F. Oram, “Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier disease,” Journal of Clinical Investigation, vol. 96, no. 1, pp. 78–87, 1995.
[22]
E. T. Alexander, C. Vedhachalam, S. Sankaranarayanan et al., “Influence of apolipoprotein A-I domain structure on macrophage reverse cholesterol transport in mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 2, pp. 320–327, 2011.
[23]
N. S. Sabeva, E. J. Rouse, and G. A. Graf, “Defects in the leptin axis reduce abundance of the ABCG5-ABCG8 sterol transporter in liver,” Journal of Biological Chemistry, vol. 282, no. 31, pp. 22397–22405, 2007.
[24]
N. R. Webb, P. M. Connell, G. A. Graf et al., “SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells,” Journal of Biological Chemistry, vol. 273, no. 24, pp. 15241–15248, 1998.
[25]
E. T. Alexander, G. L. Weibel, M. R. Joshi et al., “Macrophage reverse cholesterol transport in mice expressing ApoA-I milano,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 10, pp. 1496–1501, 2009.
[26]
T. J. F. Nieland, M. Penman, L. Dori, M. Krieger, and T. Kirchhausen, “Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 24, pp. 15422–15427, 2002.
[27]
S. Hayat and J. G. Raynes, “Serum amyloid A has little effect on hight density lipoprotein (HDL) binding to U937 monocytes but may influence HDL mediated cholesterol transfer,” Biochemical Society Transactions, vol. 25, no. 2, p. 348S, 1997.
[28]
S. P. Tam, A. Flexman, J. Hulme, and R. Kisilevsky, “Promoting export of macrophage cholesterol: the physiological role of a major acute-phase protein, serum amyloid A 2.1,” Journal of Lipid Research, vol. 43, no. 9, pp. 1410–1420, 2002.
[29]
J. A. Stonik, A. T. Remaley, S. J. Demosky, E. B. Neufeld, A. Bocharov, and H. B. Brewer, “Serum Amyloid a promotes ABCA1-dependent and ABCA1-independent lipid efflux from cells,” Biochemical and Biophysical Research Communications, vol. 321, no. 4, pp. 936–941, 2004.
[30]
D. R. Van Der Westhuyzen, L. Cai, M. C. De Beer, and F. C. De Beer, “Serum amyloid A promotes cholesterol efflux mediated by scavenger receptor B-I,” Journal of Biological Chemistry, vol. 280, no. 43, pp. 35890–35895, 2005.
[31]
S. Abe-Dohmae, K. H. Kato, Y. Kumon et al., “Serum amyloid A generates high density lipoprotein with cellular lipid in an ABCA1- or ABCA7-dependent manner,” Journal of Lipid Research, vol. 47, no. 7, pp. 1542–1550, 2006.
[32]
G. Marsche, S. Frank, J. G. Raynes, K. F. Kozarsky, W. Sattler, and E. Malle, “The lipidation status of acute-phase protein serum amyloid A determines cholesterol mobilization via scavenger receptor class B, type I,” Biochemical Journal, vol. 402, no. 1, pp. 117–124, 2007.
[33]
M. C. De Beer, A. Ji, A. Jahangiri et al., “ATP binding cassette G1-dependent cholesterol efflux during inflammation,” Journal of Lipid Research, vol. 52, no. 2, pp. 345–353, 2011.
[34]
L. Cai, M. C. De Beer, F. C. De Beer, and D. R. Van Der Westhuyzen, “Serum amyloid a is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake,” Journal of Biological Chemistry, vol. 280, no. 4, pp. 2954–2961, 2005.
[35]
J. M. Brown, T. A. Bell III, H. M. Alger et al., “Targeted depletion of hepatic ACAT2-driven cholesterol esterification reveals a non-biliary route for fecal neutral sterol loss,” Journal of Biological Chemistry, vol. 283, no. 16, pp. 10522–10534, 2008.
[36]
J. K. Kruit, T. Pl？sch, R. Havinga et al., “Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice,” Gastroenterology, vol. 128, no. 1, pp. 147–156, 2005.
[37]
J. N. van der Veen, T. H. van Dijk, C. L. J. Vrins et al., “Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol,” Journal of Biological Chemistry, vol. 284, no. 29, pp. 19211–19219, 2009.
[38]
A. E. van der Velde, C. L. J. Vrins, K. van den Oever et al., “Direct intestinal cholesterol secretion contributes significantly to total fecal neutral sterol excretion in mice,” Gastroenterology, vol. 133, no. 3, pp. 967–975, 2007.
[39]
R. E. Temel, J. K. Sawyer, L. Yu et al., “Biliary sterol secretion is not required for macrophage reverse cholesterol transport,” Cell Metabolism, vol. 12, no. 1, pp. 96–102, 2010.
[40]
N. Nijstad, T. Gautier, F. Briand, D. J. Rader, and U. J. F. Tietge, “Biliary sterol secretion is required for functional in vivo reverse cholesterol transport in mice,” Gastroenterology, vol. 140, no. 3, pp. 1043–1051, 2011.
