The acute phase response in Syrian hamsters elevates apolipoprotein serum amyloid A (apoSAA) and disrupts lipoprotein metabolism

Gonnerman, Wayne A.; Lima, May; Sipe, Jean D.; Hayes, K. C.; Cathcart, Edgar S.

doi:10.3109/13506129609014374

Cited by 16 publications

(9 citation statements)

References 31 publications

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“…The amount of SAA in the corresponding acute-phase HDL preparations used for this experiment was 29% of total apolipoprotein content. inflammation is to enhance cholesterol removal from sites of tissue destruction, whereas Gonnermann et al 32 proposed that SAA may commandeer HDL during the acute-phase response to deliver phospholipids and cholesterol to cells involved in tissue repair at sites of inflammation. Our present in vitro data, in particular a 2-fold higher selective SAA-enriched HDL-CE uptake by macrophages, provide support for the latter hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…It may be assumed that acute-phase HDL could mediate phospholipid and cholesterol/CE delivery to regenerating tissue at sites of inflammation, where neutrophils, monocytes, and macrophages are present. 31,32 This concept has been supported by the observation that acute-phase HDL binds strongly to peritoneal macrophages. 33 Alternatively, it was hypothesized that acute-phase SAA targets the HDL particle to activated macrophages, where it enhances clearance of excess cholesterol from these cells.…”

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confidence: 93%

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Role of Serum Amyloid A During Metabolism of Acute-Phase HDL by Macrophages

Artl

Marsche

Lestavel

et al. 2000

ATVB

228

188

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Abstract-The serum amyloid A (SAA) family of proteins is encoded by multiple genes that display allelic variation and a high degree of homology in mammals. Triggered by inflammation after stimulation of hepatocytes by lymphokinemediated processes, the concentrations of SAA may increase during the acute-phase reaction to levels 1000-fold greater than those found in the noninflammatory state. In addition to its role as an acute-phase reactant, SAA (104 amino acids, 12 kDa) is considered to be the precursor protein of secondary reactive amyloidosis, in which the N-terminal portion is incorporated into the bulk of amyloid fibrils. However, the association with lipoproteins of the high-density range and subsequent modulation of the metabolic properties of its physiological carrier appear to be the principal role of SAA. Because SAA may displace apolipoprotein A-I, the major protein component of native high density lipoprotein (HDL), during the acute-phase reaction, the present study was aimed at (1) investigating binding properties of native and acute-phase (SAA-enriched) HDL by J774 macrophages, (2) elucidating whether the presence of SAA on HDL particles affects selective uptake of HDL-associated cholesteryl esters, and (3) comparing cellular cholesterol efflux mediated by native and acute-phase HDL. Both the total and the specific binding at 4°C of rabbit acute-phase HDL were Ϸ2-fold higher than for native HDL. Nonlinear regression analysis revealed K d values of 7.0ϫ10 Ϫ7 mol/L (native HDL) and 3.1ϫ10Ϫ7 mol/L (acute-phase HDL), respectively. The corresponding B max values were 203 ng of total lipoprotein per milligram of cell protein (native HDL) and 250 ng of total lipoprotein per milligram of cell protein (acute-phase HDL). At 37°C, holoparticle turnover was slightly enhanced for acute-phase HDL, a fact reflected by 2-fold higher degradation rates. In contrast, the presence of SAA on HDL specifically increased (1.7-fold) the selective uptake of HDL cholesteryl esters from acute-phase HDL by J774 macrophages, a widely used in vitro model to study foam cell formation and cholesterol efflux properties. Although ligand blotting experiments with solubilized J774 membrane proteins failed to identify the scavenger receptor-BI as a binding protein for both native and acute-phase HDL, 2 binding proteins with molecular masses of 100 and 72 kDa, the latter comigrating with CD55 (also termed decay-accelerating factor), were identified. During cholesterol efflux studies, it became apparent that the ability of acute-phase HDL with regard to cellular cholesterol removal was considerably lower than that for native HDL. This was reflected by a 1.7-fold increase in /2 values (22 versus 36 hours; native versus acute-phase HDL). Our observations of increased HDL cholesteryl ester uptake and reduced cellular cholesterol efflux (acute-phase versus native HDL) suggest that displacement of apolipoprotein A-I by SAA results in considerable altered metabolic properties of its main physiological carrier. These changes in the apolipoprote...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 93%

Role of Serum Amyloid A During Metabolism of Acute-Phase HDL by Macrophages

Artl

Marsche

Lestavel

et al. 2000

ATVB

228

188

View full text Add to dashboard Cite

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“…Based on the foregoing findings, and HDL's role as a "reverse cholesterol transporter" (31,32), we postulated that SAA played a major role in modulating HDL's function and in mobilizing macrophage cholesterol during acute inflammation. Previous tissue culture studies exploring the effect of AP-HDL on macrophage cholesterol export observed either no effect or an inhibition of macrophage cholesterol efflux (33)(34)(35)(36) and concluded that AP-HDL is impaired in its ability to promote cholesterol efflux and may actually cause cholesterol loading of macrophages. All these past studies put trace quantities of radio-labeled cholesterol into macrophages, and, unfortunately, failed to use macrophages frankly laden with cholesterol, the physiologic setting in which AP-HDL and SAA are found and in which their effects should have been assessed.…”

Section: Discussionmentioning

confidence: 99%

Promoting export of macrophage cholesterol

Tam

Flexman

Hulme

et al. 2002

Journal of Lipid Research

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We show that murine macrophages that have ingested cell membranes as a source of cholesterol exhibit a marked increase in acyl-CoA:cholesterol acyl tranferase (ACAT) activity. Exposure of these macrophages to acutephase high-density lipoprotein (HDL) results in a marked reduction of ACAT and enhancement of cholesteryl ester hydrolase (CEH) activities, phenomena not seen with native HDL. These complementary but opposite effects of acutephase HDL on the two enzyme systems that regulate the balance between esterified (storage) cholesterol and unesterified (transportable) cholesterol are shown to reside with serum amyloid A (SAA) 2.1, an acute-phase apolipoprotein of HDL whose plasma concentration increases 500-to 1,000-fold within 24 h of acute tissue injury. Mild trypsin treatment of acute-phase HDL almost completely abolishes the apoliporotein-mediated effects on the cholesteryl ester cycle in cholesterol-laden macrophages. The physiological effect of SAA2.1 on macrophage cholesterol is to shift it into a transportable state enhancing its rate of export, which we confirm in tissue culture and in vivo. The export process is shown to be coupled to the ATP binding cassette transport system. Our findings integrate previous isolated observations about SAA into the sphere of cholesterol transport, establish a function for a major acute-phase protein, and offer a novel approach to mobilizing macrophage cholesterol at sites of atherogenesis.-Shui Pang Tam, Alana Flexman, Jennifer Hulme, and Robert Kisilevsky. Promoting export of macrophage cholesterol: the physiological role of a major acute-phase protein, serum amyloid A 2.1. J. Lipid Res.

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“…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 al 13 postulated that the principal role for SAA in acute inflammation is to enhance cholesterol removal from sites of tissue destruction, whereas Gonnermann et al 14 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, Khovidhunkit 15 et al commented, "Because apoSAA can displace apoA-I from HDL 16,17 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.…”

Section: See Page 1806mentioning

confidence: 99%