Transformation of Amyloid Precursor SAA to Protein AA and Incorporation in Amyloid Fibrils in Vivo

Husebekk, Anne; Skogen, Bjøŕn; Husby, Gunnar; Marhaug, G.

doi:10.1111/j.1365-3083.1985.tb01431.x

Cited by 230 publications

(137 citation statements)

References 18 publications

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“…Furthermore, recent studies have also indicated that oral ERT increased risk of dementia. 21 SAA is a precursor of amyloid fibril, 22,23 which is found to deposit in the brain of patients with Alzheimer's disease, promoting chronic neuronal inflammation and neuronal loss. 24 Whether chronic elevation in SAA during oral ERT will lead to deposition of amyloid fibrils in brain tissue and contribute to development of dementia also remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Contrasting Effects of Oral Versus Transdermal Estrogen on Serum Amyloid A (SAA) and High-Density Lipoprotein–SAA in Postmenopausal Women

Abbas¹,

Fadel²,

Wang³

et al. 2004

ATVB

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Objectives-Previous studies indicated that oral estrogen increased C-reactive protein by a first-pass hepatic effect. In this study, we determine whether the route of estrogen administration influences serum amyloid A (SAA), another acute-phase protein produced by the liver, and the SAA content of the high-density lipoprotein (HDL-SAA) in postmenopausal women. Methods and Results-In 29 postmenopausal women without coronary heart disease, we conducted a randomized crossover placebo-controlled study to compare effects of transdermal versus oral estrogen on SAA and HDL-SAA. SAA, apolipoprotein A-I, HDL, and HDL-SAA were measured before and after 8 weeks of transdermal estradiol (100 g per day), oral-conjugated estrogens (0.625 mg per day), or placebo. We found that oral estrogen significantly increased levels of SAA, HDL, and HDL-SAA, whereas transdermal estrogen reduced both SAA and HDL-SAA but had no effect on HDL in the same women. Conclusions-Oral estrogen increased SAA and altered HDL composition to contain a higher level of SAA by a first-pass hepatic mechanism. Because elevated SAA levels predict adverse prognosis in healthy postmenopausal women, and elevated HDL-SAA levels have been shown to interfere with HDL function, the route of administration may be an important consideration in minimizing side effects of estrogen replacement therapy on cardiovascular outcomes. Key Words: hormones Ⅲ inflammation Ⅲ serum amyloid A Ⅲ menopause Ⅲ HDL T he role of inflammation in the development of atherosclerosis is firmly established. Among markers of systemic inflammation, C-reactive protein (CRP) is one of the most important acute-phase proteins known to be independent predictors of adverse cardiovascular events in otherwise healthy women. 1 Recent studies by our group and others indicated that oral estrogen replacement therapy (ERT) caused a sustained increase in CRP, which may explain the increased risks of cardiovascular events of ERT in clinical trials. 2,3 This increase in CRP was avoided by transdermal estrogen, implicating a first-pass hepatic effect. See page 1741Serum amyloid A (SAA) is another acute-phase protein that determines long-term cardiovascular prognosis in women. 1 Like CRP, SAA is produced by the liver and has been shown to directly promote atherosclerosis and vascular inflammation. 4 However, unlike CRP, SAA can form a complex with high-density lipoprotein (HDL) in the plasma, and the elevated SAA content of the HDL particle (HDL-SAA) has been shown to interfere with antiatherogenic, antioxidative, and anti-inflammatory HDL function. 5 Although the influence of estrogen on CRP has been studied extensively, effects of estrogen administration on SAA are still unknown. The purpose of our present study is not only to determine whether the route of estrogen administration influences SAA levels but also HDL-SAA in postmenopausal women. MethodsThe study was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas. After informed written consent was obtai...

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Section: Discussionmentioning

confidence: 99%

Contrasting Effects of Oral Versus Transdermal Estrogen on Serum Amyloid A (SAA) and High-Density Lipoprotein–SAA in Postmenopausal Women

Abbas¹,

Fadel²,

Wang³

et al. 2004

ATVB

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“…SAA is deposited in the spleen, kidney, and liver, where it is processed, leaving the amino half to two thirds of its sequence behind in the fibril. 15,16 How SAA becomes deposited as an amyloid A protein (the 76 -amino acid N-terminal portion of SAA) is largely unknown; however, it is possible that its physiological carrier (see below) could contribute to this process.…”

mentioning

confidence: 99%

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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“…It is believed that persistently high levels of SAA during chronic inflammation may contribute to the occasional development of the potentially fatal disease reactive amyloidosis [amyloid A (AA) amyloidosis] (5). In AA amyloidosis, AA, an N-terminal (1-76) fragment of SAA (6), frequently is found to form amyloid deposits in the liver, kidney, and spleen. However, the presence, in vivo, of full-length SAA in amyloid deposits (7) and the ability of various SAA isoforms to form fibrils in vitro (8)(9)(10) suggest that proteolytic cleavage may not be a prerequisite for AA deposition but rather a postdeposition event.…”

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confidence: 99%

Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel

Wang

Lashuel

Walz

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Serum amyloid A (SAA) is a small apolipoprotein that binds to high-density lipoproteins in the serum. Although SAA seems to play a role in host defense and lipid transport and metabolism, its specific functions have not been defined. Despite the growing implications that SAA plays a role in the pathology of various diseases, a high-resolution structure of SAA is lacking because of limited solubility in the high-density lipoprotein-free form. In this study, complementary methods including glutaraldehyde cross-linking, size-exclusion chromatography, and sedimentationvelocity analytical ultracentrifugation were used to show that murine SAA2.2 in aqueous solution exists in a monomer-hexamer equilibrium. Electron microscopy of hexameric SAA2.2 revealed that the subunits are arranged in a ring forming a putative central channel. Limited trypsin proteolysis and mass spectrometry analysis identified a significantly protease-resistant SAA2.2 region comprising residues 39 -86. The isolated 39 -86 SAA2.2 fragment did not hexamerize, suggesting that part of the N terminus is involved in SAA2.2 hexamer formation. Circular-dichroism spectrum deconvolution and secondary-structure prediction suggest that SAA2.2 contains Ϸ50% of its residues in ␣-helical conformation and <10% in ␤-structure. These findings are consistent with the recent discovery that human SAA1.1 forms a membrane channel and have important implications for understanding the 3D structure, multiple functions, and pathological roles of this highly conserved protein.S erum amyloid A (SAA) proteins are a family of apolipoproteins found predominantly associated with high-density lipoprotein (HDL) in plasma (1), with different isoforms being unequally expressed constitutively and in response to inflammatory stimuli (2). Although synthesized primarily in the liver, extrahepatic tissue͞cellular expression of SAA has been widely documented (3). SAA has been linked to functions related to inflammation, pathogen defense, HDL metabolism, and cholesterol transport and thereby has been implicated (3) in several pathological conditions including atherosclerosis, rheumatoid arthritis, Alzheimer's disease, and cancer.SAA is known best for its role during the acute phase response to an inflammatory stimulus such as infection, tissue injury, and trauma (2). During active inflammation the concentration of SAA in plasma can increase up to 1,000-fold within 24 h (4). It is believed that persistently high levels of SAA during chronic inflammation may contribute to the occasional development of the potentially fatal disease reactive amyloidosis [amyloid A (AA) amyloidosis] (5). In AA amyloidosis, AA, an N-terminal (1-76) fragment of SAA (6), frequently is found to form amyloid deposits in the liver, kidney, and spleen. However, the presence, in vivo, of full-length SAA in amyloid deposits (7) and the ability of various SAA isoforms to form fibrils in vitro (8-10) suggest that proteolytic cleavage may not be a prerequisite for AA deposition but rather a postdeposition event. Of the thre...

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Transformation of Amyloid Precursor SAA to Protein AA and Incorporation in Amyloid Fibrils in Vivo

Cited by 230 publications

References 18 publications

Contrasting Effects of Oral Versus Transdermal Estrogen on Serum Amyloid A (SAA) and High-Density Lipoprotein–SAA in Postmenopausal Women

Contrasting Effects of Oral Versus Transdermal Estrogen on Serum Amyloid A (SAA) and High-Density Lipoprotein–SAA in Postmenopausal Women

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

Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel

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