doi: 10.1161/01.ATV.0000232522.47018.a6
© 2006 American Heart Association, Inc.
Editorials |
Understanding Changes in High Density Lipoproteins During the Acute Phase Response
From the Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA.
Correspondence to Brian J. Van Lenten, PhD, Room BH-307 CHS, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1679. E-mail BvanLent{at}mednet.ucla.edu
During infection and inflammation there is a cascade of reactions that occurs in the host collectively known as the acute-phase response (APR).1 Besides alterations in acute-phase reactants (plasma proteins), the APR is also associated with changes in lipoproteins.2 Increasing evidence suggests that high density lipoproteins (HDL) are a critical part of the acute phase response (APR) of the innate immune system.3 During infection and inflammation, there is a reduction in levels of several plasma proteins involved in HDL-mediated reverse cholesterol transport and inhibiting plasma lipid oxidation, such as lecithin:cholesterol acyltransferase (LCAT), cholesterol ester transfer protein, phospholipid transfer protein, hepatic lipase, apolipoprotein A-I (apoA-I), and paraoxonase (PON).2 Moreover, the composition of circulating HDL during an APR, also known as acute-phase HDL, is altered. Analysis of the lipid composition shows that acute-phase HDL is depleted in cholesterol ester but enriched in free cholesterol, triglyceride, and free tty acids.4 Changes in the phospholipid content of acute-phase HDL was shown to be more variable, having increased in one study5 but decreased in another.6 The levels of apolipoprotein J (apoJ or clusterin) and serum amyloid A (SAA) increase several fold in acute-phase HDL.7 Because of the marked changes in HDL during an APR, acute-phase HDL behaves differently from normal HDL in terms of its protective effect against atherosclerosis.8 Malle and coworkers have shown that acute-phase HDL was less effective in removing cholesterol from macrophages.9 Delivery of cholesterol ester to hepatocytes is also decreased during an APR because of changes in HDL composition and a reduction in hepatic scavenger receptor class B type.10
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A protective role for HDL in atherogenesis likely relates, in part, to antioxidant enzymes associated with it. PON has been shown to be effective in preventing metal ion–dependent oxidation of LDL and can protect against LDL oxidation in vitro.11,12 PON is also capable of destroying the biologically active lipids that are generated in LDL when LDL becomes trapped in an artery wall cell coculture system and may function similarly in the vessel wall in vivo.11,12 In rabbits, Van Lenten reported that the APR resulted in apoA-I being displaced from HDL by SAA, which was associated with a decrease in PON activity and the conversion of HDL to a proinflammatory state.7 Kisilevsky et al13 postulated that the principal role for SAA in acute inflammation is to enhance cholesterol removal from sites of tissue destruction, whereas Gonnermann et al14 proposed that SAA enrichment of HDL during the acute-phase response may cause HDL to deliver phospholipids and cholesterol to cells involved in tissue repair at sites of inflammation. In reviewing the changes in HDL induced by the APR, Khovidhunkit15 et al commented, "Because apoSAA can displace apoA-I from HDL16,17 and apoSAA-rich HDL particles are rapidly cleared from the circulation,18 it has been assumed that the several-fold increase in apoSAA content in HDL is the mechanism for the decrease in apoA-I and HDL levels. However, we have shown that the decrease in HDL is very rapid, occurring before the increase in SAA.19 Furthermore, a study in mice in which apoSAA levels were markedly increased to levels comparable to those seen in infection found no changes in HDL cholesterol or apoA-I levels.20 Thus, high levels of SAA per se do not decrease HDL or apoA-I levels in the absence of the other changes that occur during infection and inflammation."
The notion that displacement of apoA-I from HDL during an APR may contribute to a less protective form of HDL was advanced by evidence from Burger and colleagues, who demonstrated an inhibition of cellular contact between stimulated T cells and monocytes by HDL-associated apoA-I.21 This mechanism inhibits monocyte activation and therefore both tumor necrosis factor (TNF)-
and interleukin (IL)-1ß production. Noting that this inhibitory activity is present in plasma, the authors suggest that apoA-I controls the contact-mediated activation of monocytes in the blood stream. By inhibiting contact-mediated activation of monocytes, HDL-associated apoA-I displays antiinflammatory properties in a mechanism relevant to atherosclerosis.
In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology Han et al22 demonstrate in an elegant series of in vitro and in vivo studies reciprocal and coordinate regulation of serum amyloid A versus apoA-I and PON-1 by inflammation in murine hepatocytes. These authors convincingly demonstrate that cytokines coordinately increase SAA and decrease apoA-I and PON-1. These reciprocal changes appear to be promoted by NF-
B and repressed by the nuclear receptor PPAR-. As the authors note, neither apoA-I nor PON-1 promoters contain NF-B sites,23–26 and the SAA promoters do not contain PPAR response elements.27 Thus, the mechanism for this coordinate regulation may be indirect both for PPAR- and NF-B. Despite the absence of a clear mechanism for the all the steps involved, their experiments in PPAR-–deficient mice convincingly demonstrate that PPAR- does affect the expression of mouse apoA-I, and shows that PPAR activation can mitigate NF-B activation by inflammatory stimuli.
The authors propose a model whereby reciprocal changes during cytokine-mediated inflammation are regulated by an interaction between PPAR- and NF-B, inducing counter-regulatory transcriptional responses through changes in expression of their target genes. Their work also suggests that PPAR- expression exerts a chronic "braking" effect on inflammation, which can be reversed by inflammatory cytokines or the absence of PPAR- itself.
These studies22 together with the earlier studies19,20 suggest that the reduction in apoA-I and PON during the APR is most likely not simply attributable to the displacement of apoA-I particles containing PON by SAA but is an example of the extraordinary molecular complexity of the APR, which includes reciprocal and coordinate changes of many important proteins.
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Acknowledgments |
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Disclosures
MN, STR, and AMF are principals in Bruin Pharma and AMF is an officer in Bruin Pharma.
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References |
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 Top References |
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1. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999; 340: 448–454.
2. Khovidhunkit W, Memon RA, Feingold KR, Grunfeld C. Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis. 2000; 181: S462–S472.
3. Navab M, Berliner JA, Subbanagounder G, Hama S, Lusis AJ, Castellani LW, Reddy ST, Shih D, Shi W, Watson AD, Van Lenten BJ, Vora D, Fogelman AM. HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol. 2001; 21: 481–488.
4. Cabana VG, Lukens JR, Rice KS, Hawkins TJ, Getz GS. HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease. J Lipid Res. 1996; 37: 2662–2674.[Abstract]
5. Auerbach BJ, Parks JS. Lipoprotein abnormalities associated with lipopolysaccharide (LPS)-induced lecithin: cholesterol acyltransferase and lipase deficiency. J Biol Chem. 1989; 264: 10264–10270.
6. Cabana VG, Siegel JN, Sabesin SM. Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins. J Lipid Res. 1989; 30: 39–49.[Abstract]
7. Van Lenten BJ, Wagner AC, Nayak DP, Hama S, Navab M, Fogelman AM. HDL loses its anti-inflammatory properties during acute influenza A infection. Circulation. 2001; 103: 2283–2288.
8. Van Lenten BJ, Hama SY, deBeer FC, Stafforini DM, McIntyre TM, Prescott SM, La Du BN, Fogelman AM, Navab M. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J Clin Invest. 1995; 96: 2758–2767.[Medline] [Order article via Infotrieve]
9. Artl A, Marsche G, Lestavel S, Sattler W, Malle E. Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler Thromb Vase Biol. 2000; 20: 763–772.
10. Artl A, Marsche G, P. Pussinen P, G. Knipping G, Sattler W, Malle E. Impaired capacity of acute-phase high density lipoprotein particles to deliver cholesteryl ester to the human HUH-7 hepatoma cell line. Int J Biochem Cell Biol. 2002; 34: 370–381.[CrossRef][Medline] [Order article via Infotrieve]
11. Watson AD, Navab M, Hama SY, Sevanian A, Prescott SM, Stafforini DM, McIntyre TM, La Du BN, Fogelman AM, Berliner JA. Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest. 1995; 95: 774–782.[Medline] [Order article via Infotrieve]
12. Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, Navab M. Protective effect of high density lipoprotein associated PON. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995; 96: 2882–2891.[Medline] [Order article via Infotrieve]
13. Kisilevsky R, Lindhorst E, Ancsin JB, Young D, Bagshaw W. Acute phase serum amyloid A (SAA) and cholesterol transport during acute inflammation: a hypothesis. Amyloid: Int J Exp Clin Invest. 1996; 3: 252–260.
14. Gonnerman WA, Lim M, Sipe JD, Hayes KC, Cathcart ES. The acute phase response in Syrian hamsters elevates apolipoprotein serum amyloid A (apoSAA) and disrupts lipoprotein metabolism. Amyloid: Int J Exp Clin Invest. 1996; 3: 261–269.
15. Khovidhunkit W, Kim M-S, Memon RA, Shigenaga JK, Moser AH, Feingold KR, Grunfeld C. Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res. 2004; 45: 1169–1196.
16. Husebekk A, Skogen B, Husby G. High-density lipoprotein has different binding capacity for different apoproteins. The amyloidogenic apoproteins are easier to displace from high density lipoprotein. Scand J Immunol. 1988; 28: 653–658.[CrossRef][Medline] [Order article via Infotrieve]
17. Coetzee GA, Strachan AF, van der Westhuyzen DR, Hoppe HC, Jeenah MS, de Beer FC. Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition J Biol Chem. 1986; 261: 9644–9651.
18. Hoffman JS, Benditt EP. Plasma clearance kinetics of the amyloid-related high density lipoprotein apoprotein, serum amyloid protein (apoSAA), in the mouse. Evidence for rapid apoSAA clearance J Clin Invest. 1983; 71: 926–934.[Medline] [Order article via Infotrieve]
19. Ly H, Francone OL, Fielding CJ, Shigenaga JK, Moser AH, Grunfeld C, Feingold KR. Endotoxin and TNF lead to reduced plasma LCAT activity and decreased hepatic LCAT mRNA levels in Syrian hamsters. J Lipid Res. 1995; 36: 1254–1263.[Abstract]
20. Hosoai H, Webb NR, Glick JM, Tietge UJ, Purdom MS, de Beer FC, Rader DJ. Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice. J Lipid Res. 1999; 40: 648–653.
21. Hyka N, Dayer J-M, Modoux C, Kohno T, Edwards CK, Roux-Lombard P, and Burger D. Apolipoprotein A-I inhibits the production of IL-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood. 2001; 97: 2381–2389.
22. Han CY, Chiba T, Campbell JS, Faust N, Chaisson M, Orasanu G, Plutzky J, Chait A. Reciprocal and co-ordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes. Arterioscler Thromb Vasc Biol. 2006; 26; 1806–1813.[CrossRef][Medline] [Order article via Infotrieve]
23. Staels B, Auwerx J. Regulation of apo A-I gene expression by fibrates. Atherosclerosis. 1998; 137: S19–S23.
24. Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, Fruchart JC, Rubin E, Denefle P, Staels B, Branellec D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest. 1996; 97: 2408–2416.[Medline] [Order article via Infotrieve]
25. Gouedard C, Koum-Besson N, Barouki R, Morel Y. Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. Mol Pharmacol. 2003; 63: 945–956.
26. Gouedard C, Barouki R, Morel Y. Induction of the paraoxonase-1 gene expression by resveratrol. Arterioscler Thromb Vasc Biol. 2004; 24: 2378–2383.
27. Uhlar CM, Whitehead AS. Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem. 1999; 265: 501–523.[Medline] [Order article via Infotrieve]
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