Catabolism of Lipid‐Free Recombinant Apolipoprotein Serum Amyloid A by Mouse Macrophages <i>In Vitro</i> Results in Removal of the Amyloid Fibril‐Forming Amino Terminus

Elliott-Bryant, Rosemary; Liang, J S; Sipe, Jean D.; Cathcart, Edgar S.

doi:10.1046/j.1365-3083.1998.00384.x

Cited by 10 publications

(9 citation statements)

References 33 publications

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“…These calcium-binding polypeptides act to amplify pre-existing inflammatory states by their effects, via RAGE binding, on a number of pro-inflammatory cells [18]. It is of interest that S100/calgranulin has been shown to accumulate in a number of chronic inflammatory diseases, and in particular in patients with CF [23, 24]. Based on this data we speculate that the renal changes we have described in CF, mimic those of diabetic nephropathy, as a consequence of a shared terminal pathway, namely ligand binding of RAGE, albeit by S100/calgranulin, as opposed to by AGE as has been described in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

“…In CF, chronic pulmonary infection/inflammation, in combination with reduced glutathione levels, a key pulmonary antioxidant, contributes to an oxidative state [27]. AGE accumulation is therefore a potential mechanism for the changes we describe in CFRD, given their known contribution to renal damage in non-diabetic patients [23, 28]. It has also been demonstrated in experimental studies that the infusion of non-diabetic animals with AGE-albumin results in glomerular pathology indistinguishable from that seen in diabetic mellitus [29].…”

Section: Discussionmentioning

confidence: 99%

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Nodular Glomerulosclerosis in Cystic Fibrosis Mimics Diabetic Nephropathy

Westall¹,

Binder²,

Kotsimbos³

et al. 2004

Nephron Clin Pract

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Background/Aims: Despite the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator, being widely expressed throughout the kidney, there is no clearly defined renal phenotype in patients with cystic fibrosis. As patients with cystic fibrosis survive longer progressive pancreatic destruction may lead to abnormal glucose tolerance and diabetes mellitus, which in the kidney may be associated with the characteristic changes of nodular glomerulosclerosis. Methods: The adult cystic fibrosis service at the Alfred hospital consists of a cohort of 200 patients. We describe 3 cystic fibrosis patients with impaired renal function who had renal biopsies performed as part of their diagnostic work-up. All patients had fasting plasma glucose levels, oral glucose tolerance tests and measurements of HbA_1c performed to assess for the presence of cystic fibrosis-related diabetes mellitus. Results: The renal biopsies of all 3 patients showed histological changes characteristic of diabetic nephropathy. In all cases described characteristic Kimmelstiel-Wilson nodules were present. However, in all 3 patients the presence of impaired glucose tolerance and diabetes mellitus was excluded using standard biochemical diagnostic criteria. Conclusion: We describe 3 adult CF patients, who on renal biopsy had histological evidence of nodular glomerulosclerosis in the absence of abnormal glucose metabolism. We speculate that the pro-inflammatory cytokine profile, typical of cystic fibrosis, predisposes to the lesions described.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nodular Glomerulosclerosis in Cystic Fibrosis Mimics Diabetic Nephropathy

Westall¹,

Binder²,

Kotsimbos³

et al. 2004

Nephron Clin Pract

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“…For instance, the N-and C-terminal 12 and 17 residues, respectively, are unlikely to contribute to SAA2.2 hexamerization, because the proline-rich C terminus is highly solvent-exposed and most likely unstructured (30), and the N terminus is involved in HDL͞cholesterol binding (9,31). Because residues 30-42 are also exposed in human and murine SAA (32,33), the region available for hexamerization seems limited to residues 13-29 and 43-86, which are predicted to have a high ␣-helical structure content (Fig. 6A).…”

Section: Discussionmentioning

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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“…A‐SAA is probably degraded after its disassociation from HDL, as full‐length A‐SAA can be found in amyloid fibrils [260–263]. Furthermore, lipid‐free A‐SAA can be degraded [264] in vitro to form fibrils [265]. In addition, A‐SAA degradation in vivo is inhibited by lipoproteins, in particular HDL [80,266], and differences between the plasma clearance rates of A‐SAA and ApoA‐I also suggest that the former is not associated with HDL when it is degraded [83,266].…”

Section: Saa Function and Disease Associationsmentioning

confidence: 99%

Serum amyloid A, the major vertebrate acute‐phase reactant

Uhlar

Whitehead

1999

European Journal of Biochemistry

950

951

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The serum amyloid A (SAA) family comprises a number of differentially expressed apolipoproteins, acute-phase SAAs (A-SAAs) and constitutive SAAs (C-SAAs). A-SAAs are major acute-phase reactants, the in vivo concentrations of which increase by as much as 1000-fold during inflammation. A-SAA mRNAs or proteins have been identified in all vertebrates investigated to date and are highly conserved. In contrast, C-SAAs are induced minimally, if at all, during the acute-phase response and have only been found in human and mouse. Although the liver is the primary site of synthesis of both A-SAA and C-SAA, extrahepatic production has been reported for most family members in most of the mammalian species studied. In vitro, the dramatic induction of A-SAA mRNA in response to pro-inflammatory stimuli is due largely to the synergistic effects of cytokine signaling pathways, principally those of the interleukin-1 and interleukin-6 type cytokines. This induction can be enhanced by glucocorticoids. Studies of the A-SAA promoters in several mammalian species have identified a range of transcription factors that are variously involved in defining both cytokine responsiveness and cell specificity. These include NF-kB, C/EBP, YY1, AP-2, SAF and Sp1. A-SAA is also post-transcriptionally regulated. Although the precise role of A-SAA in host defense during inflammation has not been defined, many potential clinically important functions have been proposed for individual SAA family members. These include involvement in lipid metabolism/transport, induction of extracellular-matrix-degrading enzymes, and chemotactic recruitment of inflammatory cells to sites of inflammation. A-SAA is potentially involved in the pathogenesis of several chronic inflammatory diseases: it is the precursor of the amyloid A protein deposited in amyloid A amyloidosis, and it has also been implicated in the pathogenesis of atheroscelerosis and rheumatoid arthritis.

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Catabolism of Lipid‐Free Recombinant Apolipoprotein Serum Amyloid A by Mouse Macrophages In Vitro Results in Removal of the Amyloid Fibril‐Forming Amino Terminus

Cited by 10 publications

References 33 publications

Nodular Glomerulosclerosis in Cystic Fibrosis Mimics Diabetic Nephropathy

Nodular Glomerulosclerosis in Cystic Fibrosis Mimics Diabetic Nephropathy

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

Serum amyloid A, the major vertebrate acute‐phase reactant

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