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1
Shephard, E. G., F. C. de Beer, M. C. de Beer, M. S. Jeenah, G. A. Coetzee, and D. R. van der Westhuyzen. "Neutrophil association and degradation of normal and acute-phase high-density lipoprotein 3." Biochemical Journal 248, no. 3 (December 15, 1987): 919–26. http://dx.doi.org/10.1042/bj2480919.
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The interaction of normal and acute-phase high-density lipoproteins of the subclass 3 (N-HDL3 and AP-HDL3) with human neutrophils and the accompanying degradation of HDL3 apolipoproteins have been studied in vitro. The chemical composition of normal and acute-phase HDL3 was similar except that serum amyloid A protein (apo-SAA) was a major apolipoprotein in AP-HDL3 (approx. 30% of total apolipoproteins). 125I-labelled AP-HDL3 was degraded 5-10 times faster than 125I-labelled N-HDL3 during incubation with neutrophils or neutrophil-conditioned medium. Apo-SAA, like apolipoprotein A-II (apo-A-II), was more susceptible than apolipoprotein A-I (apo-A-I) to the action of proteases released from the cells. The amounts of cell-associated AP-HDL3 apolipoproteins at saturation were up to 2.8 times greater than N-HDL3 apolipoproteins; while apo-A-I was the major cell-associated apolipoprotein when N-HDL3 was bound, apo-SAA constituted 80% of the apolipoproteins bound in the case of AP-HDL3. The associated intact apo-SAA was mostly surface-bound as it was accessible to the action of exogenous trypsin. alpha 1-Antitrypsin-resistant (alpha 1-AT-resistant) cellular degradation of AP-HDL3 apolipoproteins also occurred; experiments in which pulse-chase labelling was performed or lysosomotropic agents were used indicated that insignificant intracellular degradation occurred which points to the involvement of cell-surface proteases in this degradation.
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Nel, A. E., M. C. De Beer, E. G. Shephard, A. F. Strachan, M. L. Vandenplas, and F. C. De Beer. "Phosphorylation of human serum amyloid A protein by protein kinase C." Biochemical Journal 255, no. 1 (October 1, 1988): 29–34. http://dx.doi.org/10.1042/bj2550029.
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Monokine-induced hepatic secretion of serum amyloid A protein (apo-SAA), an acute-phase reactant, is followed by rapid association with high-density lipoprotein (HDL) in plasma. Plasma clearance of apo-SAA is more rapid than any of the other HDL apolipoproteins. It has been shown that, of the acute-phase HDL3 apolipoproteins, apo-SAA preferentially associates with neutrophil membranes. HDL apolipoproteins have been shown to activate protein kinase C in endothelial cells. We therefore investigated potential phosphorylation of HDL3 apolipoproteins by protein kinase C. Apo-SAA was the only apolipoprotein phosphorylated (Km = 12 mM). Phosphorylation of the apo-SAA-containing HDL3 particle was selective for the more basic isoforms of apo-SAA (pI 7.0, 7.4, 7.5 and 8.0), with more acidic isoforms being phosphorylated when delipidated acute-phase apolipoproteins were used as substrate. However, phosphorylation was not in itself responsible for the establishment of the apo-SAA isoforms.
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Lepedda, Antonio J., Gabriele Nieddu, Elisabetta Zinellu, Pierina De Muro, Franco Piredda, Anna Guarino, Rita Spirito, Franco Carta, Francesco Turrini, and Marilena Formato. "Proteomic Analysis of Plasma-Purified VLDL, LDL, and HDL Fractions from Atherosclerotic Patients Undergoing Carotid Endarterectomy: Identification of Serum Amyloid A as a Potential Marker." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/385214.
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Apolipoproteins are very heterogeneous protein family, implicated in plasma lipoprotein structural stabilization, lipid metabolism, inflammation, or immunity. Obtaining detailed information on apolipoprotein composition and structure may contribute to elucidating lipoprotein roles in atherogenesis and to developing new therapeutic strategies for the treatment of lipoprotein-associated disorders. This study aimed at developing a comprehensive method for characterizing the apolipoprotein component of plasma VLDL, LDL, and HDL fractions from patients undergoing carotid endarterectomy, by means of two-dimensional electrophoresis (2-DE) coupled with Mass Spectrometry analysis, useful for identifying potential markers of plaque presence and vulnerability. The adopted method allowed obtaining reproducible 2-DE maps of exchangeable apolipoproteins from VLDL, LDL, and HDL. Twenty-three protein isoforms were identified by peptide mass fingerprinting analysis. Differential proteomic analysis allowed for identifying increased levels of acute-phase serum amyloid A protein (AP SAA) in all lipoprotein fractions, especially in LDL from atherosclerotic patients. Results have been confirmed by western blotting analysis on each lipoprotein fraction using apo AI levels for data normalization. The higher levels of AP SAA found in patients suggest a role of LDL as AP SAA carrier into the subendothelial space of artery wall, where AP SAA accumulates and may exert noxious effects.
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Djurec, Magdolna, Osvaldo Graña, Albert Lee, Kevin Troulé, Elisa Espinet, Lavinia Cabras, Carolina Navas, et al. "Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors." Proceedings of the National Academy of Sciences 115, no. 6 (January 19, 2018): E1147—E1156. http://dx.doi.org/10.1073/pnas.1717802115.
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Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα+ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα+ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.
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Saïle, R., C. Delpierre, P. Puchois, G. Hocke, C. Cachera, J. C. Gesquiere, A. Steinmetz, A. Tartar, and J. C. Fruchart. "Enzyme-linked immunosorbent assay for serum amyloid A apolipoprotein with use of specific antibodies against synthetic peptides." Clinical Chemistry 34, no. 9 (September 1, 1988): 1767–71. http://dx.doi.org/10.1093/clinchem/34.9.1763.
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Abstract We describe a noncompetitive enzyme-linked immunosorbent assay for amyloid A apolipoprotein in human serum (apo SAA) in which specific antibodies against synthetic peptides are used. Microtiter plates were used as solid phase and coated with affinity-purified antibodies raised against SAA1-(95-104) peptide. After incubation with delipidated plasmas, the bound apo SAA was revealed by labeled antibodies raised against SAA1-(58-69) peptide. The assay offers several advantages over existing techniques: sensitivity, specificity, simplicity, and non-use of radioisotopes. Results correlate well with those by a nephelometric method in which polyclonal antibodies are used.
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Beach, C. M., M. C. De Beer, J. D. Sipe, L. D. Loose, and F. C. De Beer. "Human serum amyloid A protein. Complete amino acid sequence of a new variant." Biochemical Journal 282, no. 2 (March 1, 1992): 615–20. http://dx.doi.org/10.1042/bj2820615.
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Serum amyloid A protein (SAA), an acute-phase reactant and apolipoprotein of high-density lipoprotein, is a polymorphic protein with six reported isoforms. These are the products of three genes, i.e., cDNA pA1, cDNA pSAA82 and genomic DNA SAAg9, the last two being allelic variants at a single locus. We have identified an individual with additional novel SAA isoforms on isoelectric-focusing analysis. By using 3-bromo-3-methyl-2-(2′-nitrophenylsulphenyl)-indolenine (BNPS-skatole) cleavage of the protein at tryptophan residues we obtained the complete amino acid sequence of a novel isoform. Additional cleavage by endoproteinase Asp-N allowed verification of the tryptophan residues and complete amino acid sequence of both isoforms. The suitability of this approach to the rapid sequencing of SAA was demonstrated. Sequence analysis and quantification suggest that these isoforms are the result of the first confirmed allelic variation at the SAA1 locus. We designate the protein products of this allele SAA1 beta (pI 6.1) and SAA1 beta des-Arg (pI 5.6).
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Jayaraman, Shobini, Donald L. Gantz, Christian Haupt, and Olga Gursky. "Serum amyloid A forms stable oligomers that disrupt vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis." Proceedings of the National Academy of Sciences 114, no. 32 (July 25, 2017): E6507—E6515. http://dx.doi.org/10.1073/pnas.1707120114.
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Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding by binding to plasma high-density lipoproteins. However, unbound soluble SAA is intrinsically disordered and is either rapidly degraded or forms amyloid in a lysosome-initiated process. Although acidic pH promotes amyloid fibril formation by this and many other proteins, the molecular underpinnings are unclear. We used an array of spectroscopic, biochemical, and structural methods to uncover that at pH 3.5–4.5, murine SAA1 forms stable soluble oligomers that are maximally folded at pH 4.3 with ∼35% α-helix and are unusually resistant to proteolysis. In solution, these oligomers neither readily convert into mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a manner typical of apolipoproteins. Rather, these oligomers undergo an α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt these vesicles, suggesting a membranolytic potential. Our results provide an explanation for the lysosomal origin of AA amyloidosis. They suggest that high structural stability and resistance to proteolysis of SAA oligomers at pH 3.5–4.5 help them escape lysosomal degradation, promote SAA accumulation in lysosomes, and ultimately damage cellular membranes and liberate intracellular amyloid. We posit that these soluble prefibrillar oligomers provide a missing link in our understanding of the development of AA amyloidosis.
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Fleischer, Jacklyn G., Dan Rossignol, Gordon A. Francis, Teddy Chan, Melvyn Lynn, and Kishor M. Wasan. "Deactivation of the lipopolysaccharide antagonist eritoran (E5564) by high-density lipoprotein-associated apolipoproteins." Innate Immunity 18, no. 1 (March 7, 2011): 171–78. http://dx.doi.org/10.1177/1753425910394395.
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Lipid A, the active moiety of LPS, exerts its effects through interaction with TLR4, triggering a signalling cascade that results in the release of pro-inflammatory cytokines. Eritoran is a lipid A analogue that competes with LPS for binding to TLR4; however, after intravenous administration, it undergoes a time-dependent deactivation as a consequence of binding to high-density lipoproteins (HDLs). The site of eritoran association with HDL remains unknown. Therefore the aim of this study was to determine if HDL-associated apolipoproteins A1, A2, serum amyloid A (SAA) and C1, inhibit the ability of eritoran to block LPS-induced TNF-α release from whole blood. Eritoran activity after LPS stimulation in human whole blood was assessed in the presence of reconstituted HDL (rHDL) containing different apos. In rHDL, the major apolipoproteins in both the healthy and septic state, A1 and SAA, caused a significant reduction in eritoran antagonistic activity and had a greater effect than minor apolipoproteins A2 and C1. Apolipoproteins associated with HDL are likely to facilitate eritoran deactivation. Apolipoproteins A1 and SAA should be of particular focus as they are the major apos found on HDL in both the healthy and septic state. Further evaluation of the physical association between apolipoproteins and eritoran should be explored.
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Marsche, Gunther, Sǎsa Frank, John G. Raynes, Karen F. Kozarsky, Wolfgang Sattler, and Ernst Malle. "The lipidation status of acute-phase protein serum amyloid A determines cholesterol mobilization via scavenger receptor class B, type I." Biochemical Journal 402, no. 1 (January 25, 2007): 117–24. http://dx.doi.org/10.1042/bj20061406.
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During the acute-phase reaction, SAA (serum amyloid A) replaces apoA-I (apolipoprotein A-I) as the major HDL (high-density lipoprotein)-associated apolipoprotein. A remarkable portion of SAA exists in a lipid-free/lipid-poor form and promotes ABCA1 (ATP-binding cassette transporter A1)-dependent cellular cholesterol efflux. In contrast with lipid-free apoA-I and apoE, lipid-free SAA was recently reported to mobilize SR-BI (scavenger receptor class B, type I)-dependent cellular cholesterol efflux [Van der Westhuyzen, Cai, de Beer and de Beer (2005) J. Biol. Chem. 280, 35890–35895]. This unique property could strongly affect cellular cholesterol mobilization during inflammation. However, in the present study, we show that overexpression of SR-BI in HEK-293 cells (human embryonic kidney cells) (devoid of ABCA1) failed to mobilize cholesterol to lipid-free or lipid-poor SAA. Only reconstituted vesicles containing phospholipids and SAA promoted SR-BI-mediated cholesterol efflux. Cholesterol efflux from HEK-293 and HEK-293[SR-BI] cells to lipid-free and lipid-poor SAA was minimal, while efficient efflux was observed from fibroblasts and CHO cells (Chinese-hamster ovary cells) both expressing functional ABCA1. Overexpression of SR-BI in CHO cells strongly attenuated cholesterol efflux to lipid-free SAA even in the presence of an SR-BI-blocking IgG. This implies that SR-BI attenuates ABCA1-mediated cholesterol efflux in a way that is not dependent on SR-BI-mediated re-uptake of cholesterol. The present in vitro experiments demonstrate that the lipidation status of SAA is a critical factor governing cholesterol acceptor properties of this amphipathic apolipoprotein. In addition, we demonstrate that SAA mediates cellular cholesterol efflux via the ABCA1 and/or SR-BI pathway in a similar way to apoA-I.
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SCHREIBER, Barbara M., Mara VEVERBRANTS, Richard E. FINE, Jan K. BLUSZTAJN, Mario SALMONA, Apurva PATEL, and Jean D. SIPE. "Apolipoprotein serum amyloid A down-regulates smooth-muscle cell lipid biosynthesis." Biochemical Journal 344, no. 1 (November 8, 1999): 7–13. http://dx.doi.org/10.1042/bj3440007.
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The addition of acute-phase apolipoprotein serum amyloid A (SAA) to cultured aortic smooth-muscle cells caused a decrease in the incorporation of [14C]acetate into lipids. Optimal inhibition of lipid biosynthesis was achieved with 2 μM SAA, and the effect was maintained for up to 1 week when SAA was included in the culture medium. Lipid extracts were subjected to TLC and it was determined that the SAA-induced decrease in [14C]acetate incorporation into lipids was attributable to decreases in cholesterol, phospholipid and triglyceride levels. The accumulated mass of cholesterol and phospholipid in SAA-treated cultures was significantly less than that of controls, with no change in the accumulated protein. Moreover, SAA had no effect on either protein synthesis or DNA synthesis, suggesting that SAA specifically alters lipid synthesis. By using a peptide corresponding to the cholesterol-binding domain of acute-phase SAA (amino acids 1-18), it was shown that this region of the molecule was as effective as the full-length protein in decreasing lipid synthesis and the accumulation of cholesterol and phospholipid. The implications of these findings for atherosclerosis and Alzheimer's disease are discussed.
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Baltz, M. L., I. F. Rowe, D. Caspi, W. G. Turnell, and M. B. Pepys. "Acute-phase high-density lipoprotein in the rat does not contain serum amyloid A protein." Biochemical Journal 242, no. 1 (February 15, 1987): 301–3. http://dx.doi.org/10.1042/bj2420301.
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Serum amyloid A protein (SAA) is an acute-phase apolipoprotein of high-density lipoprotein (HDL). Its N-terminal sequence is identical with that of amyloid A protein (AA), the subunit of AA amyloid fibrils. However, rats do not develop AA amyloidosis, and we report here that neither normal nor acute-phase rat HDL contains a protein corresponding to SAA of other species. mRNA coding for a sequence homologous with the C-terminal but not with the N-terminal part of human SAA is synthesized in greatly increased amounts in acute-phase rat liver. These observations indicate that the failure of rats to develop AA amyloid results from the absence of most of the AA-like part of their SAA-like protein, and that the N-terminal portion of SAA probably contains the lipid-binding sequences.
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Shimano, Shitsuko, Ryunosuke Ohkawa, Mayu Nambu, Mai Sasaoka, Azusa Yamazaki, Yuki Fujii, Yuna Horiuchi, et al. "Marked Changes in Serum Amyloid A Distribution and High-Density Lipoprotein Structure during Acute Inflammation." BioMed Research International 2021 (January 27, 2021): 1–8. http://dx.doi.org/10.1155/2021/9241259.
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High-density lipoprotein- (HDL-) cholesterol measurements are generally used in the diagnosis of cardiovascular diseases. However, HDL is a complicated heterogeneous lipoprotein, and furthermore, it can be converted into dysfunctional forms during pathological conditions including inflammation. Therefore, qualitative analysis of pathophysiologically diversified HDL forms is important. A recent study demonstrated that serum amyloid A (SAA) can remodel HDL and induce atherosclerosis not only over long periods of time, such as during chronic inflammation, but also over shorter periods. However, few studies have investigated rapid HDL remodeling. In this study, we analyzed HDL samples from patients undergoing orthopedic surgery inducing acute inflammation. We enrolled 13 otherwise healthy patients who underwent orthopedic surgery. Plasma samples were obtained on preoperative day and postoperative days (POD) 1-7. SAA, apolipoprotein A-I (apoA-I), and apolipoprotein A-II (apoA-II) levels in the isolated HDL were determined. HDL particle size, surface charge, and SAA and apoA-I distributions were also analyzed. In every patient, plasma SAA levels peaked on POD3. Consistently, the HDL apoA-I : apoA-II ratio markedly decreased at this timepoint. Native-polyacrylamide gel electrophoresis and high-performance liquid chromatography revealed the loss of small HDL particles during acute inflammation. Furthermore, HDL had a decreased negative surface charge on POD3 compared to the other timepoints. All changes observed were SAA-dependent. SAA-dependent rapid changes in HDL size and surface charge were observed after orthopedic surgery. These changes might affect the atheroprotective functions of HDL, and its analysis can be available for the qualitative HDL assessment.
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Cai, Xiaoping, Gulfam Ahmad, Farjaneh Hossain, Yuyang Liu, XiaoSuo Wang, Joanne Dennis, Ben Freedman, and Paul K. Witting. "High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice." International Journal of Molecular Sciences 21, no. 4 (February 15, 2020): 1316. http://dx.doi.org/10.3390/ijms21041316.
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Serum amyloid A (SAA) promotes endothelial inflammation and dysfunction that is associated with cardiovascular disease and renal pathologies. SAA is an apoprotein for high-density lipoprotein (HDL) and its sequestration to HDL diminishes SAA bioactivity. Herein we investigated the effect of co-supplementing HDL on SAA-mediated changes to vascular and renal function in apolipoprotein E-deficient (ApoE−/−) mice in the absence of a high-fat diet. Male ApoE−/− mice received recombinant human SAA or vehicle (control) by intraperitoneal (i.p.) injection every three days for two weeks with or without freshly isolated human HDL supplemented by intravenous (i.v.) injection in the two weeks preceding SAA stimulation. Aorta and kidney were harvested 4 or 18 weeks after commencement of treatment. At 4 weeks after commencement of treatment, SAA increased aortic vascular cell adhesion molecule (VCAM)-1 expression and F2-isoprostane level and decreased cyclic guanosine monophosphate (cGMP), consistent with SAA stimulating endothelial dysfunction and promoting atherosclerosis. SAA also stimulated renal injury and inflammation that manifested as increased urinary protein, kidney injury molecule (KIM)-1, and renal tissue cytokine/chemokine levels as well as increased protein tyrosine chlorination and P38 MAPkinase activation and decreased in Bowman’s space, confirming that SAA elicited a pro-inflammatory phenotype in the kidney. At 18 weeks, vascular lesions increased significantly in the cohort of ApoE−/− mice treated with SAA alone. By contrast, pretreatment of mice with HDL decreased SAA pro-inflammatory activity, inhibited SAA enhancement of aortic lesion size and renal function, and prevented changes to glomerular Bowman’s space. Taken together, these data indicate that supplemented HDL reduces SAA-mediated endothelial and renal dysfunction in an atherosclerosis-prone mouse model.
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Ji, Ailing, Xuebing Wang, Victoria P. Noffsinger, Drew Jennings, Maria C. de Beer, Frederick C. de Beer, Lisa R. Tannock, and Nancy R. Webb. "Serum amyloid A is not incorporated into HDL during HDL biogenesis." Journal of Lipid Research 61, no. 3 (January 8, 2020): 328–37. http://dx.doi.org/10.1194/jlr.ra119000329.
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Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral vector. Alternatively, we incubated primary hepatocytes from SAA-deficient mice with purified SAA. We analyzed conditioned media to determine the lipidation status of endogenously produced and exogenously added SAA. Examining the migration of lipidated species, we found that SAA is lipidated and forms nascent particles that are distinct from apoA-I-containing particles and that apoA-I lipidation is unaltered when SAA is overexpressed or added to the cells, indicating that SAA is not incorporated into apoA-I-containing HDL during HDL biogenesis. Like apoA-I formation, generation of SAA-containing particles was dependent on ABCA1, but not on scavenger receptor class B type I. Hepatocytes degraded significantly more SAA than apoA-I. Taken together, our results indicate that SAA’s lipidation and metabolism by the liver is independent of apoA-I and that SAA is not incorporated into HDL during HDL biogenesis.
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Vallejo, Abigail, Belal Chami, Joanne Dennis, Martin Simone, Gulfam Ahmad, Adrian Abdo, Arpeeta Sharma, et al. "NFκB Inhibition Mitigates Serum Amyloid A-Induced Pro-Atherogenic Responses in Endothelial Cells and Leukocyte Adhesion and Adverse Changes to Endothelium Function in Isolated Aorta." International Journal of Molecular Sciences 20, no. 1 (December 28, 2018): 105. http://dx.doi.org/10.3390/ijms20010105.
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The acute phase protein serum amyloid A (SAA) is associated with endothelial dysfunction and early-stage atherogenesis. Stimulation of vascular cells with SAA increases gene expression of pro-inflammation cytokines and tissue factor (TF). Activation of the transcription factor, nuclear factor kappa-B (NFκB), may be central to SAA-mediated endothelial cell inflammation, dysfunction and pro-thrombotic responses, while targeting NFκB with a pharmacologic inhibitor, BAY11-7082, may mitigate SAA activity. Human carotid artery endothelial cells (HCtAEC) were pre-incubated (1.5 h) with 10 μM BAY11-7082 or vehicle (control) followed by SAA (10 μg/mL; 4.5 h). Under these conditions gene expression for TF and Tumor Necrosis Factor (TNF) increased in SAA-treated HCtAEC and pre-treatment with BAY11-7082 significantly (TNF) and marginally (TF) reduced mRNA expression. Intracellular TNF and interleukin 6 (IL-6) protein also increased in HCtAEC supplemented with SAA and this expression was inhibited by BAY11-7082. Supplemented BAY11-7082 also significantly decreased SAA-mediated leukocyte adhesion to apolipoprotein E-deficient mouse aorta in ex vivo vascular flow studies. In vascular function studies, isolated aortic rings pre-treated with BAY11-7082 prior to incubation with SAA showed improved endothelium-dependent vasorelaxation and increased vascular cyclic guanosine monophosphate (cGMP) content. Together these data suggest that inhibition of NFκB activation may protect endothelial function by inhibiting the pro-inflammatory and pro-thrombotic activities of SAA.
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Steel, D. M., J. T. Rogers, M. C. DeBeer, F. C. DeBeer, and A. S. Whitehead. "Biosynthesis of human acute-phase serum amyloid A protein (A-SAA) in vitro: the roles of mRNA accumulation, poly(A) tail shortening and translational efficiency." Biochemical Journal 291, no. 3 (May 1, 1993): 701–7. http://dx.doi.org/10.1042/bj2910701.
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Human ‘acute-phase’ serum amyloid A protein (A-SAA) is a major acute-phase reactant (APR) and an apolipoprotein of high density lipoprotein 3 (HDL3). We have examined several parameters of A-SAA biosynthesis in PLC/PRF/5 hepatoma cells in response to monocyte conditioned medium (MoCM) and dual treatment with interleukin-1 beta and interleukin-6 (IL-1 beta + IL-6). Treatment of PLC/PRF/5 cells with MoCM or IL-1 beta + IL-6 caused a dramatic and rapid increase in A-SAA mRNA and protein synthesis; A-SAA mRNA was first detectable at 3 h, with peak levels reached by 24 h. A-SAA mRNA accumulation is accompanied by a gradual and homogeneous decrease in the length of the A-SAA poly(A) tail; the poly(A) tail shortening does not apparently affect the intrinsic stability of A-SAA mRNA. Analysis of RNA isolated from the ribonucleoprotein, monosome and polysome fractions of cytokine-treated PLC/PRF/5 cells showed that most A-SAA mRNA was associated with small polyribosomes, regardless of time post-stimulus, suggesting that the translational efficiency of A-SAA mRNA is constant throughout cytokine-driven induction. Moreover, the transit time of A-SAA protein out of the cell is also constant throughout the time course of induction. These data provide evidence of a paradox with regard to the transcriptional upregulation of A-SAA by IL-1 beta + IL-6 and the relative synthesis of A-SAA protein and suggest a role for post-transcriptional control of A-SAA biosynthesis during the acute phase.
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Tape, Cynthia, and Robert Kisilevsky. "Apolipoprotein A-I and apolipoprotein SAA half-lives during acute inflammation and amyloidogenesis." Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism 1043, no. 3 (April 1990): 295–300. http://dx.doi.org/10.1016/0005-2760(90)90030-2.
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Malle, Ernst, Armin Steinmetz, and John G. Raynes. "Serum amyloid A (SAA): an acute phase protein and apolipoprotein." Atherosclerosis 102, no. 2 (September 1993): 131–46. http://dx.doi.org/10.1016/0021-9150(93)90155-n.
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JENSEN, Liselotte E., and Alexander S. WHITEHEAD. "Regulation of serum amyloid A protein expression during the acute-phase response." Biochemical Journal 334, no. 3 (September 15, 1998): 489–503. http://dx.doi.org/10.1042/bj3340489.
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The acute-phase (AP) serum amyloid A proteins (A-SAA) are multifunctional apolipoproteins which are involved in cholesterol transport and metabolism, and in modulating numerous immunological responses during inflammation and the AP response to infection, trauma or stress. During the AP response the hepatic biosynthesis of A-SAA is up-regulated by pro-inflammatory cytokines, and circulating concentrations can increase by up to 1000-fold. Chronically elevated A-SAA concentrations are a prerequisite for the pathogenesis of secondary amyloidosis, a progressive and fatal disease characterized by the deposition in major organs of insoluble plaques composed principally of proteolytically cleaved A-SAA, and may also contribute to physiological processes that lead to atherosclerosis. There is therefore a requirement for both positive and negative control mechanisms that permit the rapid induction of A-SAA expression until it has fulfilled its host-protective function(s) and subsequently ensure that its expression can be rapidly returned to baseline. These mechanisms include modulation of promoter activity involving, for example, the inducer nuclear factor κB (NF-κB) and its inhibitor IκB, up-regulatory transcription factors of the nuclear factor for interleukin-6 (NF-IL6) family and transcriptional repressors such as yin and yang 1 (YY1). Post-transcriptional modulation involving changes in mRNA stability and translation efficiency permit further up- and down-regulatory control of A-SAA protein synthesis to be achieved. In the later stages of the AP response, A-SAA expression is effectively down-regulated via the increased production of cytokine antagonists such as the interleukin-1 receptor antagonist (IL-1Ra) and of soluble cytokine receptors, resulting in less signal transduction driven by pro-inflammatory cytokines.
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Griffiths, Kayleigh, Agnieszka Pazderska, Mohammed Ahmed, Anne McGowan, Alexander P. Maxwell, Jane McEneny, James Gibney, and Gareth J. McKay. "Type 2 Diabetes in Young Females Results in Increased Serum Amyloid A and Changes to Features of High Density Lipoproteins in Both HDL2 and HDL3." Journal of Diabetes Research 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/1314864.
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Persons with type 2 diabetes mellitus (T2DM) have an elevated risk of atherosclerosis. High-density lipoproteins (HDL) normally protect against cardiovascular disease (CVD), but this may be attenuated by serum amyloid A (SAA). In a case-control study of young females, blood samples were compared between subjects with T2DM (n=42) and individuals without T2DM (n=42). SAA and apolipoprotein AI (apoAI) concentrations, paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) activities were measured in the serum and/or HDL2 and HDL3 subfractions. SAA concentrations were higher in T2DM compared to controls: serum (30 mg/L (17, 68) versus 15 mg/L (7, 36); p=0.002), HDL2 (1.0 mg/L (0.6, 2.2) versus 0.4 mg/L (0.2, 0.7); p<0.001), and HDL3 (13 mg/L (8, 29) versus 6 mg/L (3, 13); p<0.001). Serum-PON-1 activity was lower in T2DM compared to that in controls (38,245 U/L (7025) versus 41,109 U/L (5690); p=0.043). CETP activity was higher in T2DM versus controls in HDL2 (232.6 μmol/L (14.1) versus 217.1 μmol/L (25.1); p=0.001) and HDL3 (279.5 μmol/L (17.7) versus 245.2 μmol/L (41.2); p<0.001). These results suggest that individuals with T2DM have increased SAA-related inflammation and dysfunctional HDL features. SAA may prove to be a useful biomarker in T2DM given its association with elevated CVD risk.
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Capozzalo, M. M., J. C. Kim, J. K. Htoo, C. F. M. de Lange, B. P. Mullan, C. F. Hansen, J. W. Resink, and J. R. Pluske. "Pigs experimentally infected with an enterotoxigenic strain of Escherichia coli have improved feed efficiency and indicators of inflammation with dietary supplementation of tryptophan and methionine in the immediate post-weaning period." Animal Production Science 57, no. 5 (2017): 935. http://dx.doi.org/10.1071/an15289.
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This experiment tested the hypothesis that pigs challenged with an enterotoxigenic strain of E. coli (ETEC) will improve performance by dietary supplementation of sulfur amino acids (SAA) and tryptophan (Trp) above the current recommended levels in the immediate post-weaning period. Male pigs (n = 96) weighing 6.2 ± 0.78 kg (mean ± s.d.) and weaned at 21 days were stratified into one of four treatments based on weaning weight (n = 24). Four diets were formulated [11.2 MJ NE/kg; 20.1% crude protein, 1.25% standardised ileal digestible (SID) lysine (Lys)] according to a 2 × 2 factorial arrangement of treatments with two levels of SID SAA : Lys ratio (0.52 vs 0.60) and two levels of SID Trp : Lys ratio (0.16 vs 0.24). Diets did not contain any antimicrobial compounds. Pigs were individually housed and were fed diets for 14 days after weaning. Pigs were infected with ETEC (3.44 × 108 CFU/mL, serotype O149 : K91 : K88) on Days 5, 6, and 7 after weaning. Pigs were bled on Days 5, 8 and 14 and subsequently analysed for plasma levels of acute-phase proteins, urea, cytokines (Days 5 and 8 only) and amino acids (Days 5 and 8 only). Increasing Trp (P = 0.036) and SAA (P = 0.028) improved feed conversion ratio, and combined supplementation of SAA and Trp further improved FCR than individual supplementation of either SAA or Trp (P = 0.092). Dietary treatments had no impact on the incidence of post-weaning diarrhoea (P > 0.05). Increasing SAA increased shedding of ETEC on Days 12 and 14 after weaning (P < 0.019). Increasing dietary Trp reduced the intensity of inflammation (as measured by APP Index = [(C-reactive protein × PigMAP)/apolipoprotein A1]) immediately after infection with ETEC (P < 0.05), while increasing dietary SAA reduced the APP index on 24 h and 7 days after ETEC infection (P < 0.05). Increasing dietary SAA reduced plasma levels of interferon-gamma regardless of dietary Trp or day of sampling (P = 0.043). Increasing dietary SAA decreased plasma urea (PU) levels on Days 5, 8 and 14 (P < 0.05). These data indicate that Trp supplementation reduced the intensity of inflammation and SAA supplementation decreased the pro-inflammatory interferon-gamma response and improved protein utilisation, as measured by PU, whereas supplementation with both Trp and SAA improved feed conversion ratio.
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Dubois, D. Y., and C. L. Malmendier. "Non-competitive enzyme-linked immunosorbent assay for human apolipoprotein SAA or S." Journal of Immunological Methods 112, no. 1 (August 1988): 71–75. http://dx.doi.org/10.1016/0022-1759(88)90035-x.
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Griffin, John H., Jose A. Fernandez, Ranjeet Kumar Sinha, Darlene J. Elias, and Hiroshi Deguchi. "Plasma Constitutive Serum Amyloid A4 Is Procoagulant and Is Elevated in Venous Thrombosis Patients." Blood 126, no. 23 (December 3, 2015): 3486. http://dx.doi.org/10.1182/blood.v126.23.3486.3486.
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Abstract Regulation of thrombin generation by the factors (F) Xa:Va complex is key for achieving hemostasis and avoiding thrombosis, i.e., for the hemostatic balance. Plasma lipoproteins and minor abundance lipids can influence the hemostatic balance. For example, oxidized LDL is procoagulant, HDL is anticoagulant as an APC:protein S cofactor, certain glycosphingolipids are anticoagulant cofactors, and acyl carnitines and lysosulfatides inhibit the FXa;Va complex. To identify novel lipoprotein factors that affect FXa:Va activity (prothrombinase (IIase) activity), lipoprotein fractions from ten adult varied subjects were made by ultracentrifugation and, following dialysis into Hepes-buffered saline, screened for their procoagulant activity in purified IIase assays. Each lipoprotein fraction, except that from one subject (#939) with only 22% activity, similarly enhanced thrombin generation by IIase. SDS page analysis of these lipoprotein fractions showed a very low level of one protein band (14 kDa) for subject #939. Proteomics analysis of that band from normal lipoprotein fractions implied this 14 kDa band was constitutive serum amyloid A4 (SAA4). The biologic functions of SAA4 are unclear. To assess its procoagulant activity, recombinant 14 kDa SAA4 was studied in various coagulation assays. When SAA4 was added to IIase assays, it caused a robust procoagulant activity in the presence of FVa but not in the absence of FVa. Plasma-based coagulation assays, done without phospholipids added, were also used, including FXIa-induced thrombin generation, and FXa-1-stage clotting assays. Recombinant SAA4 was mildly or strongly procoagulant in these plasma-based assays. SAA4 dose-dependently shortened the FXa-induced clotting time from 320 sec to 55 sec; and SAA4 increased thrombin generation by 15 % in normal plasma and by 85 % in plasma from subject #939. Direct interactions between recombinant SAA4 and purified FXa were studied using SPR (Octet Red™) with immobilized-FXa subjected to titrations of SAA4. Kinetic constants gave a value for Kd apparent of 25 nM for SAA4 binding to FXa. Thus, SAA4 binds FXa and is procoagulant by enhancing IIase activity. We then assessed potential clinical relevance of SAA4's procoagulant activity. SAA4 is a plasma apolipoprotein, mainly made in the liver, with a constant plasma level of 4 µM. It is not an acute phase protein, unlike SAA1 and SAA2. SAA4 contains 112 residues and plasma contains two monomeric isoforms (14 kDa and 19 kDa) due to the absence or presence of N-glycosylation at Asn-76. The plasma levels of monomeric SAA4 (combined 14 and 19 kDa isoforms) were determined by quantitative IR immunoblotting (non-reduced SDS PAGE) using the Odyssey IR imaging system (Li-Cor Biosciences) for 110 venous thrombosis (VTE) subjects and 110 matched controls from the Scripps Venous Thrombosis Registry. The Registry samples were from male and female adults without cancer or lipid altering drugs who were < 55 yrs old and gave fasting blood samples > 3 months after the clinical event (see H. Deguchi et al, BLOOD 2015). When the relative fluorescence unit (RFU) values for SAA4 14 and 19 kDa monomer bands for 110 normal subjects were normalized to a median of 100 %, patients with VTE had significantly higher plasma levels of monomeric SAA4 (median 116.4 RFU vs median 100 RFU, p=0.0005) (see median values in Figure). The odds ratio (OR) for the 75%-ile cut-off was 2.1 (95% CI = 1.2 - 3.8, p=0.01) (see Figure). Thus, SAA4 monomers are elevated in VTE patients compared to matched controls for the Scripps Venous Thrombosis Registry. Further studies are needed to replicate this finding and to gather more data towards deciphering whether the link between elevated SAA4 and VTE is causal, consequential or coincidental. However, the fact that recombinant 14 kDa SAA4 binds FXa and is procoagulant in purified IIase assays and in plasma-based clotting assays provides biological plausibility for a causal prothrombotic role for SAA4. These findings also raise the possibility that SAA4 procoagulant activity might contribute to normal hemostasis. Further studies are needed to clarify the details for the procoagulant effects of SAA4 on coagulation pathways. In summary, these results show that elevated monomeric plasma levels of SAA4 are strongly linked to VTE in adults (< 55 yrs old) and that SAA4 itself is a potential enhancer of thrombin generation in plasma. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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BEKAERT, E. D., E. DOLE, D. Y. DUBOIS, M. E. BOUMA, J.-F. LONTIE, R. KALLEL, C. L. MALMENDIER, and M. AYRAULT-JARRIER. "Alterations in lipoprotein density classes in infantile visceral Leishmaniasis: presence of apolipoprotein SAA." European Journal of Clinical Investigation 22, no. 3 (March 1992): 190–99. http://dx.doi.org/10.1111/j.1365-2362.1992.tb01825.x.
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D’Arrigo, Joseph S. "Biomimetic Nanocarrier Targeting Drug(s) to Upstream-Receptor Mechanisms in Dementia: Focusing on Linking Pathogenic Cascades." Biomimetics 5, no. 1 (March 20, 2020): 11. http://dx.doi.org/10.3390/biomimetics5010011.
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Past published studies have already documented that, subsequent to the intravenous injection of colloidal lipid nanocarriers, apolipoprotein (apo)A-I is adsorbed from the blood onto the nanoparticle surface. The adsorbed apoA-I mediates the interaction of the nanoparticle with scavenger receptors on the blood–brain barrier (BBB), followed by receptor-mediated endocytosis and subsequent transcytosis across the BBB. By incorporating the appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.e., SR-BI), and crosses the BBB. Documented similarities in lipid composition between naturally occurring high-density lipoproteins (HDL) and the artificial biomimetic (nanoemulsion) nanocarrier particles can partially simulate or mimic the known heterogeneity (i.e., subpopulations or subspecies) of HDL particles. Such biomedical application of colloidal drug-nanocarriers can potentially be extended to the treatment of complex medical disorders like dementia. The risk factors for dementia trigger widespread inflammation and oxidative stress; these two processes involve pathophysiological cascades which lead to neuronal Ca2+ increase, neurodegeneration, gradual cognitive/memory decline, and eventually (late-onset) dementia. In particular, more recent research indicates that chronic inflammatory stimulus in the gut may induce (e.g., via serum amyloid A (SAA)) the release of proinflammatory cytokines. Hence, an effective preventive and therapeutic strategy could be based upon drug targeting toward a major SAA receptor responsible for the SAA-mediated cell signaling events leading to cognitive decline and eventually Alzheimer’s disease or (late-onset) dementia.
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HUSEBEKK, A., B. SKOGEN, and G. HUSBY. "Characterization of Amyloid Proteins AA and SAA as Apolipoproteins of High Density Lipoprotein (HDL)." Scandinavian Journal of Immunology 25, no. 4 (April 1987): 375–81. http://dx.doi.org/10.1111/j.1365-3083.1987.tb02203.x.
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Moin, Abu Saleh Md, Hassan Kahal, Ahmed Al-Qaissi, Nitya Kumar, Thozhukat Sathyapalan, Stephen L. Atkin, and Alexandra E. Butler. "Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia." BMJ Open Diabetes Research & Care 9, no. 1 (April 2021): e002211. http://dx.doi.org/10.1136/bmjdrc-2021-002211.
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IntroductionHypoglycemia in type 2 diabetes (T2D) may increase risk for Alzheimer’s disease (AD), but no data on changes in AD-related proteins with differing degrees of hypoglycemia exist. We hypothesized that milder prolonged hypoglycemia would cause greater AD-related protein changes versus severe transient hypoglycemia.Research design and methodsTwo prospective case-control induced hypoglycemia studies were compared: study 1, hypoglycemic clamp to 2.8 mmol/L (50 mg/dL) for 1 hour in 17 subjects (T2D (n=10), controls (n=7)); study 2, hypoglycemic clamp to 2.0 mmol/L (36 mg/dL) undertaken transiently and reversed in 46 subjects (T2D (n=23), controls (n=23)). Blood sampling at baseline, hypoglycemia and 24-hour post-hypoglycemia, with proteomic analysis of amyloid-related proteins performed.ResultsIn control subjects, the percentage change from baseline to hypoglycemia differed between study 1 and study 2 for 5 of 11 proteins in the AD-related panel: serum amyloid A1 (SAA1) (p=0.009), pappalysin (PAPPA) (p=0.002), apolipoprotein E2 (p=0.02), apolipoprotein E3 (p=0.03) and apolipoprotein E4 (p=0.02). In controls, the percentage change from baseline to 24 hours differed between studies for two proteins: SAA1 (p=0.003) and PAPPA (p=0.004); however, after Bonferroni correction only SAA1 and PAPPA remain significant. In T2D, there were no differential protein changes between the studies.ConclusionsThe differential changes in AD-related proteins were seen only in control subjects in response to iatrogenic induction of hypoglycemic insults of differing length and severity and may reflect a protective response that was absent in subjects with T2D. Milder prolonged hypoglycemia caused greater AD-related protein changes than severe acute hypoglycemia in control subjects.Trial registration numbersNCT02205996, NCT03102801.
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Yamada, Toshiyuki, Jyunji Sato, Kazuhiko Kotani, and Masafumi Tanaka. "Influence of Polymorphism on Glycosylation of Serum Amyloid A4 Protein." Biochemistry Research International 2014 (2014): 1–4. http://dx.doi.org/10.1155/2014/527254.
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Serum amyloid A4 (SAA4) is a constitutive apolipoprotein of high-density lipoprotein. It exhibits N-linked glycosylation in its second half. There are both glycosylated and nonglycosylated forms in plasma and the ratio of these two forms varies among individuals. This study was conducted to examine the influence of genetic polymorphism of SAA4 on its glycosylation status. In 55 healthy subjects, SAA4 polymorphism was analyzed by PCR combined direct sequencing and its glycosylation status was analyzed by immunoblotting. The results showed that the percentage of glycosylation in subjects with amino acid substitutions at positions 71 and/or 84 was significantly (P<0.05) higher than that in subjects with the wild type. The polymorphism had no influence on the plasma concentration of SAA4. These findings suggest that the changes in protein structures alter the efficiency of glycosylation in the SAA4 molecule. The functional implication of this should be of interest.
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Chan, Dick C., P. Hugh R. Barrett, Esther M. M. Ooi, Juying Ji, Doris T. Chan, and Gerald F. Watts. "Very Low Density Lipoprotein Metabolism and Plasma Adiponectin as Predictors of High-Density Lipoprotein Apolipoprotein A-I Kinetics in Obese and Nonobese Men." Journal of Clinical Endocrinology & Metabolism 94, no. 3 (March 1, 2009): 989–97. http://dx.doi.org/10.1210/jc.2008-1457.
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Abstract Context: Hypercatabolism of high-density lipoprotein (HDL) apolipoprotein (apo) A-I results in low plasma apoA-I concentration. The mechanisms regulating apoA-I catabolism may relate to alterations in very low density lipoprotein (VLDL) metabolism and plasma adiponectin and serum amyloid A protein (SAA) concentrations. Objective: We examined the associations between the fractional catabolic rate (FCR) of HDL-apoA-I and VLDL kinetics, plasma adiponectin, and SAA concentrations. Study Design: The kinetics of HDL-apoA-I and VLDL-apoB were measured in 50 obese and 37 nonobese men using stable isotopic techniques. Results: In the obese group, HDL-apoA-I FCR was positively correlated with insulin, homeostasis model of assessment for insulin resistance (HOMA-IR) score, triglycerides, VLDL-apoB, and VLDL-apoB production rate (PR). In the nonobese group, HDL-apoA-I FCR was positively correlated with triglycerides, apoC-III, VLDL-apoB, and VLDL-apoB PR and negatively correlated with plasma adiponectin. Plasma SAA was not associated with HDL-apoA-I FCR in either group. In multiple regression analyses, VLDL-apoB PR and HOMA-IR score, and VLDL-apoB PR and adiponectin were independently predictive of HDL-apoA-I FCR in the obese and nonobese groups, respectively. HDL-apoA-I FCR was positively and strongly associated with HDL-apoA-I PR in both groups. Conclusions: Variation in VLDL-apoB production, and hence plasma triglyceride concentrations, exerts a major effect on the catabolism of HDL-apoA-I. Insulin resistance and adiponectin may also contribute to the variation in HDL-apoA-I catabolism in obese and nonobese subjects, respectively. We also hypothesize that apoA-I PR determines a steady-state, lowered plasma of apoA-I, which may reflect a compensatory response to a primary defect in the catabolism of HDL-apoA-I due to altered VLDL metabolism.
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Duarte-Delgado, Nancy P., Tania P. Lujan, Álvaro Arbeláez-Cortés, Jenny García-Valencia, Adriana Zapata, Mauricio Rojas, Mauricio Restrepo-Escobar, Gloria Vásquez, and Blanca L. Ortiz-Reyes. "Identification of Levels of Serum Amyloid A and Apolipoprotein A1 in Serum Proteomic Analysis of Neuropsychiatric Systemic Lupus Erythematosus Patients." Autoimmune Diseases 2018 (November 21, 2018): 1–7. http://dx.doi.org/10.1155/2018/6728541.
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Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) has multiple pathogenic mechanisms that cause diverse manifestations and whose diagnosis is challenging because of the absence of appropriate diagnostic tests. In the present study the application of proteomics using two-dimensional electrophoresis (2D) and mass spectrometry (MS) allowed the comparison of the protein profile of the serum low and high abundance protein fractions of NPSLE patients (NPSLE group) and SLE without neuropsychiatric syndromes (SLE group), Neuropsychiatric syndromes not associated with SLE (NPnoSLE groups), and healthy controls (CTRL group). The gels obtained were digitalized and analyzed with the PDQuest software. The statistical analysis of the spots was performed using the nonparametric Kruskal Wallis and Dunn's multiple comparison tests. Two spots showed significant differences and were identified by MS. Spot 4009 was significantly lower in NPSLE with regard to NPnoSLE (p= 0,004) and was identified as apolipoprotein A1 (APOA1) (score 809-1132). Spot 8001 was significantly higher in NPSLE regarding CTRL and NPnoSLE (p= 0,01 y 0,03, respectively) and was identified as serum amyloid A (SAA) (score 725-2488). The proinflammatory high density lipoproteins (HDL) have been described in SLE. In this HDL the decrease of APOA1 is followed by an increase in SAA. This altered level of both proteins may be related to the inflammatory state that is characteristic of an autoimmune disease like SLE, but this is not specific for NPSLE.
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Bains, Yasmin, Russell Caccavello, Kazuhiko Kotani, and Alejandro Gugliucci. "Paraoxonase 1, HDL Subclasses and Post Surgery Acute Inflammation: A Pilot Study." Antioxidants 8, no. 6 (June 22, 2019): 192. http://dx.doi.org/10.3390/antiox8060192.
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High density lipoproteins (HDL) structure and function studies are needed to better understand the heterogeneous nature of the HDL particle, and its interaction with associated proteins such as apolipoprotein A-1 (ApoA-1), paraoxonase 1 (PON1) and the environment. Our study assesses the effects of acute inflammation on PON1 and HDL subclasses in post-surgical colorectal cancer patients. PON1 was measured kinetically through its arylesterase and lactonase activity and HDL sub-classes were measured using Quantimetrix Lipoprint® System. White blood cells (WBC) counts, c-reactive protein (CRP) and serum amyloid A (SAA) levels were also analyzed using standard techniques. Our findings show that baseline PON1 activity is lower in colorectal cancer patients and significant reductions are observed in the acute inflammatory state post-surgery. PON1 changes are also inversely related to inflammatory markers such as SAA and CRP. In addition, our preliminary findings show that small and intermediate HDL decreases post-op Day 1. In conclusion, our study demonstrates the effects of chronic and acute inflammation on PON1. Specifically, PON1 arylesterase and lactonase activity is lower in states of chronic inflammation and further decreased in the acute inflammatory state. Additionally, in our limited sample size, while changes in PON1 and HDL subclasses may be variable in the acute inflammatory period, small HDL decreased with a loss of PON1 activity in the subacute phase.
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Xu, Zhen E., Yaxi Chen, Ailong Huang, Zac Varghese, John F. Moorhead, Feng Yan, Stephen H. Powis, Qiu Li, and Xiong Z. Ruan. "Inflammatory stress exacerbates lipid-mediated renal injury in ApoE/CD36/SRA triple knockout mice." American Journal of Physiology-Renal Physiology 301, no. 4 (October 2011): F713—F722. http://dx.doi.org/10.1152/ajprenal.00341.2010.
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Both lipids and inflammation play important roles in the progression of kidney disease. This study was designed to investigate whether inflammation exacerbates lipid accumulation via LDL receptors (LDLr), thereby causing renal injury in C57BL/6J mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE/CD36/scavenger receptor A triple KO mice. The mice were given a subcutaneous casein injection to induce inflammatory stress. After 14 wk, terminal blood samples were taken for renal function, lipid profiles, amyloid A (SAA), and IL-6 assays. Lipid accumulation in kidneys was visualized by oil red O staining. Fibrogenic molecule expression in kidneys was examined. There was a significant increase in serum SAA and IL-6 in the all casein-injected mice compared with respective controls. Casein injection reduced serum total cholesterol, LDL cholesterol, and HDL cholesterol and caused lipid accumulation in kidneys from three types of mice. The expression of LDLr and its regulatory proteins sterol-responsive element-binding protein (SREBP) 2 and SREBP cleavage-activating protein (SCAP) were upregulated in inflamed mice compared with controls. Casein injection induced renal fibrosis accompanied by increased expression of fibrogenic molecules in the triple KO mice. These data imply that inflammation exacerbates lipid accumulation in the kidney by diverting lipid from the plasma to the kidney via the SCAP-SREBP2-LDLr pathway and causing renal injury. Low blood cholesterol levels, resulting from inflammation, may be associated with high risk for chronic renal fibrosis.
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Yuditskaya, Susan, Gerard Hoehn, Anthony Suffredini, Xiuli Xu, Peter Munson, Mark Gladwin, and Gregory J. Kato. "Proteomic Identification of Dysregulated Apolipoprotein Expression in Pulmonary Hypertension Secondary to Sickle Cell Disease." Blood 106, no. 11 (November 16, 2005): 3168. http://dx.doi.org/10.1182/blood.v106.11.3168.3168.
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Abstract Pulmonary hypertension (PHT) is emerging as a major complication and independent risk factor for sudden death among adults with sickle cell disease (SCD). The identification of novel plasma markers of PHT might allow for earlier diagnosis and more convenient screening than offered by the current use of Doppler echocardiography to identify patients with high tricuspid regurgitant jet velocity (TRV). We used surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) to search for plasma biomarkers of PHT from clinical specimens. A cohort of 27 homozygous SCD patients with PHT (mean TRV=3.1±0.4 m/sec) was compared with a group of 28 homozygous SCD patients without PHT (mean TRV=1.4±0.5 m/sec), selected for similar age, gender and renal function. Plasma samples were fractionated on anion exchange columns by step pH elution (pH 3–9, organic) and applied to solid-phase protein chip surfaces (Ciphergen Biosystems ProteinChips). Univariate and multivariate analysis of SELDI-TOF data was accomplished by Random Forest classification/regression (RF), stepwise logistical regression, and Spearman correlations with clinically measured parameters. The identity of significant protein species was confirmed through MALDI-TOF and or LC-MS/MS. Results and conclusions: SELDI-TOF MS analysis resulted in 28 sets of 162 spectra each, resolving 955 peaks per patient. RF and stepwise logistical regression modeling of these peaks consistently showed lower abundance of a 28.1 kDa protein in PHT patients (p<0.0001), identified by MALDI-TOF MS and LC-MS/MS as the oxidant scavenging protein apolipoprotein A-I (apo A-I). The 28.1 kDa intensities also correlated strongly with clinical assays of apo A-I (r=0.58, p<0.0001) and HDL levels (r=0.50, p=0.0001). Comparison of PHT prevalence between patients whose apo A-I levels fell in the lowest quartile indicated a risk ratio (RR) of 2.0 compared to the upper quartile (p=0.06). Patients in the upper quartile of apo B levels had a higher prevalence of PHT than the lowest quartile (RR 2.3, p=0.05), with even higher risk indicated by a high ratio of apo B/apo A-I (RR 3.3, p=0.006), all known to be risk indicators in cardiovascular disease without SCD. In addition, a 13.4 kDa peak, identified as the inflammatory marker serum amyloid A-4 (SAA-4) by LC-MS/MS, was also important by RF and was abundant in the PHT positive group (p=0.0006). An 8.9 kDa peak, significant in combination with 28.1 kDa by stepwise logistical regression (ROC area=0.88; p=0.007) was identified by LC-MS/MS as apolipoprotein A-II. These results implicate the apolipoprotein pathway in the development of PHT vasculopathy in sickle cell disease. Their known function in regulating oxidative species supports the proposed role of oxidant stress in the sickle cell vasculopathy. Our findings are consistent with published data indicating that an apo A-I mimetic dramatically improves blood flow in the sickle cell mouse. Further studies of these apolipoproteins are warranted to validate their potential mechanistic involvement in sickle vasculopathy and as predictive markers of PHT.
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Lebrazi, H., H. Lahrach, H. Souhaili, H. Taki, A. Derouiche, and R. Saile. "Tu-P10:436 Evidence for the presence of intact serum amyloid a apolipoprotein (APO SAA) in amyloid deposits." Atherosclerosis Supplements 7, no. 3 (January 2006): 280. http://dx.doi.org/10.1016/s1567-5688(06)81137-2.
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Millar, Courtney L., Gregory H. Norris, Addison Vitols, Chelsea Garcia, Samantha Seibel, Liya Anto, and Christopher N. Blesso. "Dietary Egg Sphingomyelin Prevents Aortic Root Plaque Accumulation in Apolipoprotein-E Knockout Mice." Nutrients 11, no. 5 (May 21, 2019): 1124. http://dx.doi.org/10.3390/nu11051124.
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Western-style diets have been linked with dyslipidemia and inflammation, two well-known risk factors associated with cardiovascular disease (CVD). Dietary sphingomyelin (SM) has been reported to modulate gut microbiota, and lower serum lipids and inflammation in mice on Western-style diets. However, few studies have examined if nutritionally-relevant intake of dietary SM can impact atherosclerosis progression. Thus, the aim of this study was to determine if incorporating 0.1% (w/w) egg SM (ESM) (equivalent to ~750 mg/day in humans) into a high-fat (45% kcal), cholesterol-enriched diet (HFD) could prevent atheroprogression in apoE−/− mice (n = 15/group). We found that mice fed with the ESM-rich diet had significantly lower epididymal fat mass (−46%) and tended to have higher spleen weights (+15%). There were no significant differences in serum lipids between groups. However, ESM-fed mice had significantly lower alanine aminotransferase (ALT) activity. Additionally, ESM-fed mice displayed significantly less aortic root lipid accumulation (−31%) compared to controls. This improvement in atherosclerosis was paired with over a two-fold reduction in circulating serum amyloid A (SAA) in ESM-fed mice. Finally, there was also a modulation of the gut microbiota with ESM supplementation. ESM may have the potential to prevent atherosclerosis, however further research in the clinical setting is warranted.
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Popeijus, Herman E., Willem Zwaan, Jehad Z. Tayyeb, and Jogchum Plat. "Potential Contribution of Short Chain Fatty Acids to Hepatic Apolipoprotein A-I Production." International Journal of Molecular Sciences 22, no. 11 (June 1, 2021): 5986. http://dx.doi.org/10.3390/ijms22115986.
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Apolipoprotein A-I (ApoA-I) is the major protein of high density lipoprotein (HDL) particles and has a crucial role in reverse cholesterol transport (RCT). It has been postulated that elevating production of de novo ApoA-I might translate into the formation of new functional HDL particles that could lower cardiovascular disease (CVD) risk via RCT. During inflammation, serum ApoA-I concentrations are reduced, which contributes to the development of dysfunctional HDL particles as Serum Amyloid A (SAA) overtakes the position of ApoA-I within the HDL particles. Therefore, instead of elevating serum HDL cholesterol concentrations, rescuing lower serum ApoA-I concentrations could be beneficial in both normal and inflamed conditions. Several nutritional compounds, amongst others short chain fatty acids (SCFAs), have shown their capacity to modulate hepatic lipoprotein metabolism. In this review we provide an overview of HDL and more specific ApoA-I metabolism, SCFAs physiology and the current knowledge regarding the influence of SCFAs on ApoA-I expression and synthesis in human liver cells. We conclude that the current evidence regarding the effect of SCFAs on ApoA-I transcription and secretion is promising, however there is a need to investigate which dietary fibres could lead to increased SCFAs formation and consequent elevated ApoA-I concentrations.
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Plubell, Deanna L., Alex M. Fenton, Sara Rosario, Paige Bergstrom, Phillip A. Wilmarth, Wayne M. Clark, Neil A. Zakai, et al. "High-Density Lipoprotein Carries Markers That Track With Recovery From Stroke." Circulation Research 127, no. 10 (October 23, 2020): 1274–87. http://dx.doi.org/10.1161/circresaha.120.316526.
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Rationale: Prospective cohort studies question the value of HDL-C (high-density lipoprotein cholesterol) for stroke risk prediction. Objective: Investigate the relationship between long-term functional recovery and HDL proteome and function. Methods and Results: Changes in HDL protein composition and function (cholesterol efflux capacity) in patients after acute ischemic stroke at 2 time points (24 hours, 35 patients; 96 hours, 20 patients) and in 35 control subjects were measured. The recovery from stroke was assessed by 3 months, the National Institutes of Health Stroke Scale and modified Rankin scale scores. When compared with control subject after adjustments for sex and HDL-C levels, 12 proteins some of which participate in acute phase response and platelet activation (APMAP [adipocyte plasma membrane-associated protein], GPLD1 [phosphate inositol-glycan specific phospholipase D], APOE [apolipoprotein E], IHH [Indian hedgehog protein], ITIH4 [inter-alpha-trypsin inhibitor chain H4], SAA2 [serum amyloid A2], APOA4 [apolipoprotein A-IV], CLU [clusterin], ANTRX2 [anthrax toxin receptor 2], PON1 [serum paraoxonase/arylesterase], SERPINA1 [alpha-1-antitrypsin], and APOF [apolipoprotein F]) were significantly (adjusted P <0.05) altered in stroke HDL at 96 hours. The first 8 of these proteins were also significantly altered at 24 hours. Consistent with inflammatory remodeling, cholesterol efflux capacity was reduced by 32% ( P <0.001) at both time points. Baseline stroke severity adjusted regression model showed that changes within 96-hour poststroke in APOF, APOL1, APMAP, APOC4 (apolipoprotein C4), APOM (apolipoprotein M), PCYOX1 (prenylcysteine oxidase 1), PON1, and APOE correlate with stroke recovery scores ( R 2 =0.38–0.73, adjusted P <0.05). APOF ( R 2 =0.73) and APOL1 ( R 2 =0.60) continued to significantly correlate with recovery scores after accounting for tPA (tissue-type plasminogen activator) treatment. Conclusions: Changes in HDL proteins during early acute phase of stroke associate with recovery. Monitoring HDL proteins may provide clinical biomarkers that inform on stroke recuperation.
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de Beer, M. C., T. Yuan, M. S. Kindy, B. F. Asztalos, P. S. Roheim, and F. C. de Beer. "Characterization of constitutive human serum amyloid A protein (SAA4) as an apolipoprotein." Journal of Lipid Research 36, no. 3 (March 1995): 526–34. http://dx.doi.org/10.1016/s0022-2275(20)39886-2.
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Vermaat, J., I. van der Tweel, N. Mehra, S. Sleijfer, J. Y. Engwegen, C. M. Korse, J. H. Schellens, J. B. Haanen, J. H. Beijnen, and E. E. Voest. "Use of serum proteins identified by proteomics to predict prognosis in patients with metastatic renal cell cancer (mRCC) and comparison to the currently used MSKCC survival model." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 11078. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11078.
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11078 Background: In mRCC the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model (Motzer et al.,JCO2002) is widely used for clinical trial design and patient management. To improve this model, we searched for serum proteins associated with overall survival (OS) using proteomics and determined their potential contribution to the composition of better prognostic models. Methods: Sera from 125 mRCC patients, mostly interferon-treated, collected between 2001–2006 in three Dutch Cancer Centers, were screened by SELDI-TOF mass spectrometry (MS). Identified proteins were analyzed for their association with OS by Cox regression analysis and Kaplan-Meier curves. Three proteins were subsequently validated with conventional ELISAs and immunoturbidimetry. Computed Cox PH regression models were individually compared with the Akaike's Information Criteria (AIC). The final model was statistically bootstrapped to strengthen its validity. Results: SELDI-TOF MS successfully detected eleven prognostic proteins associated with OS. The strongest prognostic proteins, apolipoprotein A-II (ApoA2), serum amyloid alpha (SAA), and transthyretin were validated by alternative methods and confirmed for their association with OS (p=7.4×10-9, p=3.2×10-8 and p=0.0002, respectively). Stepwise multivariable Cox regression analysis provided an optimal combination of prognostic factors; ApoA2, SAA, LDH, performance status and number of metastasis sites. Subsequent categorization of patients into three risk groups generated a novel survival model that robustly predicts patient prognosis (AIC=684 and p=5.8×10-15) with increased accuracy compared to the MSKCC model (AIC=719, p=2.0×10-7). Bootstrapping our model resulted in an optimism correction of 0.04 (R2=0.45). Initiating systemic therapy according to novel proposed model instead of the MSKCC model would result in a change of treatment in 14% of the patients. Conclusions: Using proteomics, serum proteins associated with OS in mRCC patients can be identified. Incorporating some of these factors together with traditional risk factors yields a prognostic model outperforming the MSKCC risk model thereby further improving patients’ management. No significant financial relationships to disclose.
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Gruys, E., P. C. J. Tooten, and M. H. M. Kuijpers. "Lung, ileum and heart are predilection sites for AApoAII amyloid deposition in CD-1 Swiss mice used for toxicity studies. Pulmonary amyloid indicates AApoAII." Laboratory Animals 30, no. 1 (January 1, 1996): 28–34. http://dx.doi.org/10.1258/002367796780745018.
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Amyloid deposits represent frequent histological findings in SPF strains of mice mainly used for toxicological studies. Usually, these are deposits of reactive amyloid (AA-amyloid) derived from the acute phase protein serum amyloid A (SAA). The SAA is an apoprotein of high density lipoprotein (apoSAA). Senescence-accelerated amyloid (ASsam) occurs in a special strain of mice. This type of amyloid is derived from apolipoprotein-AII and, therefore, is called AApoAII. Recently, C57B1/Ka control mice not treated for long duration with immunosuppressive agents, were found to have developed AApoAII-amyloidosis with a predilection for the deposits in the ileum (HogenEsch et al. 1993). In the present study, SPF CD-1 Swiss outbred mice, used for chronic toxicity experiments, were investigated. Amyloidosis was diagnosed by haematoxylin and eosin staining. The tissue localization of amyloid was recorded and confirmed by Congo red staining. The chemical type of amyloid was investigated by peroxidase antiperoxidase (PAP)-immunostaining using anti-murine AA and anti-murine AApoAII antibodies. Those animals which died during the study and the mice killed at end of the experiment, aged 18 months, from treated as well as non-treated control groups, showed AApoAII-amyloid deposits with similar prevalence. The AApoAII amyloid had organ predilection for gut, heart and lung tissue. A group of animals was euthanazed intercurrently at a young age, since they suffered from spontaneous dermatitis associated with Staphylococcus aureus infection. Sixty-eight percent had reactive amyloid deposits found primarily in spleen, liver, kidney and gut. From these findings and literature data on various other mouse strains, it is concluded that in mice used for toxicity studies, AA and AApoAII types of amyloidosis may be expected. The deposition patterns of these types of amyloid are slightly different. AA-amyloid has a predilection for spleen, liver, gut and kidney, and is often associated with inflammatory lesions of the skin, whereas masses of amyloid in lung, heart and ileum suggest AApoAII. Pulmonary amyloid appears to represent the most reliable deposition criterion for discriminating between both types of amyloidosis.
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Yamada, Toshiyuki, Atsufumi Wada, Tetsuji Yamaguchi, Yoshihisa Itoh, and Tadashi Kawai. "Automated measurement of a constitutive isotype of serum amyloid A/SAA4 and comparison with other apolipoproteins." Journal of Clinical Laboratory Analysis 11, no. 6 (1997): 363–68. http://dx.doi.org/10.1002/(sici)1098-2825(1997)11:6<363::aid-jcla10>3.0.co;2-u.
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Dinic, Miroslav, Rados Zecevic, Zoran Hajdukovic, Mirjana Mijuskovic, Predrag Djuric, Zoran Jovic, Aleksandra Grdinic, et al. "Psoriasis is the independent factor for early atherosclerosis: A prospective study of cardiometabolic risk profile." Vojnosanitetski pregled 73, no. 12 (2016): 1094–101. http://dx.doi.org/10.2298/vsp150510134d.
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Background/Aim. Psoriasis as multisystemic inflammatory dis-ease is related with an increased cardiometabolic risk. The aim of the study was to analyze risk biomarkers, peripheral and renal arteries ultrasonography and echocardiography for subclinical atherosclerosis and metabolic disease in 106 subjects (66 psoriasis patients and 40 controls, 20 eczema patients and 20 healthy volunteers). Methods. In all exameenes following parameters were analyzed: body mass index (BMI), C-reactive protein, D-dimer, serum amyloid A (SAA), apolipoprotein (Apo) A1, ApoB, ApoB/Apo A1 index, fasting glucose, C-peptide, fasting insulinemia, homeostatic model assessment-insulin resistance (HOMA-IR), HOMA-?-cell, lipid profile, serum uric acid concentration (SUAC), 24-h proteinuria and microalbuminuria. Carotid, brachial, femoral and renal arteries ultrasonography, as well as echocardiography was also performed. Results. Five of 66 (7.6%) psoriasis patients had metabolic syndrome (not present in both control groups). The following variables were increased in patients with psoriasis compared to both control groups: BMI (p = 0.012), insulinemia (p < 0.001), HOMA-IR (p = 0.003), HOMA-? cell (p < 0.001), SUAC (p = 0.006), ApoB/ApoA1 ra-tio (p = 0.006) and microalbuminuria (p < 0.001). Also, increased C-peptide (p = 0.034), D-dimer (p = 0.029), triglycerides (p = 0.044), SAA (p = 0.005) and decreased ApoA1 (p = 0.014) were found in the psoriasis patients compared to healthy controls. HDL cholesterol was decreased in the psoriasis patients compared to the control group of eczema patients (p = 0.004). Common carotid (CIMT) and femoral artery intima-media thickness (FIMT) was significantly greater (p < 0.001) and the maximal flow speed (cm/s) in brachial artery significantly de-creased (p = 0.017) in the patients with psoriasis in comparison to both control groups. In multivariate logistic regression analysis, after the adjustment for confounding variables, the most important predictor of CIMT and FIMT was the diagnosis of psoriasis (p < 0.001). Conclusion. Cardiometabolic risk biomarkers and ultrasonographic signs of early atherosclerosis are correlated with the diagnosis of psoriasis, and not to generalized eczema. Psoriasis was found to be an independent risk factor for subclinical atherosclerosis. <br><br><font color="red"><b> This article has been corrected. Link to the correction <u><a href="http://dx.doi.org/10.2298/VSP1803334E">10.2298/VSP1803334E</a><u></b></font>
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Wallner, Marlies, Rodrig Marculescu, Daniel Doberer, Michael Wolzt, Oswald Wagner, Libor Vitek, Andrew C. Bulmer, and Karl-Heinz Wagner. "Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome." Clinical Science 125, no. 5 (May 10, 2013): 257–64. http://dx.doi.org/10.1042/cs20120661.
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Recent epidemiological and clinical data show protection from CVD (cardiovascular disease), all-cause mortality and cancer in subjects with GS (Gilbert's syndrome), which is characterized by a mildly elevated blood bilirubin concentration. The established antioxidant effect of bilirubin, however, contributes only in part to this protection. Therefore we investigated whether mildly elevated circulating UCB (unconjugated bilirubin) is associated with altered lipid metabolism. The study was performed on GS and age- and gender-matched healthy subjects (n=59 per group). Full lipoprotein profile, TAG (triacylglycerols), Apo (apolipoprotein)-A1, Apo-B, lipoprotein(a), the subfractions of LDL (low-density lipoprotein) and selected pro-inflammatory mediators were analysed. A hyperbilirubinaemic rodent model (Gunn rats, n=40) was investigated to further support the presented human data. GS subjects had significantly (P<0.05) improved lipid profile with reduced total cholesterol, LDL-C (LDL-cholesterol), TAG, low- and pro-atherogenic LDL subfractions (LDL-1+LDL-2), Apo-B, Apo-B/Apo-A1 ratio and lower IL-6 (interleukin 6) and SAA (serum amyloid A) concentrations (P=0.094). When the control and GS groups were subdivided into younger and older cohorts, older GS subjects demonstrated reduced lipid variables (total cholesterol and LDL-C, TAG and LDL-C subfractions, Apo-B/Apo-A1 ratio; P<0.05; Apo-B: P<0.1) compared with controls. These data were supported by lipid analyses in the rodent model showing that Gunn rat serum had lower total cholesterol (2.29±0.38 compared with 1.27±0.72 mM; P<0.001) and TAG (1.66±0.67 compared with 0.99±0.52 mM; P<0.001) concentrations compared with controls. These findings indicate that the altered lipid profile and the reduced pro-inflammatory status in hyperbilirubinaemic subjects, particularly in the older individuals, probably contribute additionally to the commonly accepted beneficial antioxidant effects of bilirubin in humans.
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Lundahl, Björn, Camilla Skoglund-Andersson, Muriel Caslake, Dorothy Bedford, Philip Stewart, Anders Hamsten, Christopher J. Packard, and Fredrik Karpe. "Microsomal triglyceride transfer protein −493T variant reduces IDL plus LDL apoB production and the plasma concentration of large LDL particles." American Journal of Physiology-Endocrinology and Metabolism 290, no. 4 (April 2006): E739—E745. http://dx.doi.org/10.1152/ajpendo.00376.2005.
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The microsomal triglyceride transfer protein (MTP) is essential for the synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins. We investigated the role the MTP −493G/T gene polymorphism in determining the apoB-100 secretion pattern and LDL heterogeneity in healthy human subjects. Groups of carriers of the T and the G variants ( n = 6 each) were recruited from a cohort of healthy 50-yr-old men. Kinetic studies were performed by endogenous [2H3]leucine labeling of apoB and subsequent quantification of the stable isotope incorporation. apoB production rates, metabolic conversions, and eliminations were calculated by multicompartmental modeling (SAAM-II). LDL subfraction distribution was analyzed in the entire cohort ( n = 377). Carriers of the MTP −493T allele had lower plasma LDL apoB and lower concentration of large LDL particles [LDL-I: 136 ± 57 (TT) vs. 175 ± 55 (GG) mg/l, P < 0.01]. Kinetic modeling suggested that MTP −493T homozygotes had a 60% lower direct production rate of intermediate-density lipoprotein (IDL) plus LDL compared with homozygotes for the G allele ( P < 0.05). No differences were seen in production rates of large and small VLDL, nor were there any differences in metabolic conversion or elimination rates of apoB between the genotype groups. This study shows that a polymorphism in the MTP gene affects the spectrum of endogenous apoB-containing lipoprotein particles produced in humans. Reduced direct production of LDL plus IDL appears to be related to lower plasma concentrations of large LDL particles.
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Mollee, Peter, Patricia Renaut, Samuel Boros, Dorothy Loo, and Michelle Hill. "Diagnosis Of Amyloidosis Subtype By Laser-Capture Microdissection (LCM) and Tandem Mass Spectrometry (MS) Proteomic Analysis." Blood 122, no. 21 (November 15, 2013): 5295. http://dx.doi.org/10.1182/blood.v122.21.5295.5295.
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Abstract Aim Correct identification of the protein that is causing amyloidosis is crucial for clinical management. Current standard diagnostic methods have limited ability to detect the full range of amyloid forming proteins. We assessed combining specific sampling of amyloid deposits by LCM and analysis of tryptic digests by tandem MS proteomic analysis to determine whether the majority of amyloidosis clinical samples can be correctly classified as reported by the Mayo Clinic pathology department. Methods We studied 58 cases of well characterised amyloid deposition and 10 cases in which the amyloid subtype was unable to be diagnosed with confidence. For all specimens, 10µm sections of formalin-fixed paraffin embedded tissue were stained with Congo Red using a standard technique. LCM was performed using an Arcturus XT instrument with an infrared capture laser. Proteins were digested with trypsin and peptides were analysed by nano-liquid chromatography-coupled tandem mass spectrometry using a Chip CUBE-QTOF. Database searching was performed using Spectrum Mill (Agilent) with the NCBInr human protein database. Protein identification cut-offs were protein score > 11, peptide score > 10 and % scored peak intensity >60. Results Biopsy sites included: GIT (n=16), cardiac (n=12), soft tissue (n=8), renal (n=9), liver (n=3) and other (n=20). The amyloid subtype was able to be determined in 64 cases analysed. In 7 of these cases a second sample or second LCM was required as the first analysis was non-diagnostic. In 4 cases the amyloidogenic protein was not identified mostly due to the amyloid deposits being very small. Proteins identified included immunoglobulin light chain (localised amyloid n=6, systemic AL n=32), transthyretin (senile amyloid n=17, hereditary ATTR n=2), serum amyloid A (AA n=4), fibrinogen (AFib n=1), TGFb (corneal lattice amyloid n=1) and semenogelin (seminal vesicle amyloid n=1). Three diagnostically challenging cases are detailed as examples of the utility of LCM and tandem MS. The first case had extensive gastrointestinal amyloidosis and no evidence of clonal light chain disease; negative kappa, lambda, SAA and transthyretin immunohistochemistry; and negative genetic studies. Tandem MS revealed immunoglobulin lambda light chain type. The second diagnostically challenging case had: isolated renal amyloidosis with a positive AA stain and kappa restricted serum free light chains. Tandem MS revealed serum amyloid A2 protein. The third case had: cardiac, neurological and gastrointestinal involvement; and equivocal immunohistochemistry. Tandem MS demonstrated transthyretin and genetic studies showed a A97S ATTR mutation. Various other proteins were identified by tandem MS in amyloid extracts. Of particular interest is the presence of proteins typically known to be co-located in amyloid deposits which helps confirm that the microdissected tissue is amyloid. Typical amyloid-associated proteins were identified in the following number of cases: SAP (n=36), apolipoprotein A4 (n=42), vitronectin (n=44), apolipoprotein E (n=40) and clusterin (n=21). Various types of collagen were frequently present (n=29) and various, presumably contaminating, keratins were identified (n=24). Conclusion LCM and tandem MS allows correct typing of amyloid deposits in the majority of clinical biopsy samples. Disclosures: No relevant conflicts of interest to declare.
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Hong, Meiling, Aiping Jiang, Na Li, Weihao Li, Haitao Shi, Kenneth B. Storey, and Li Ding. "Comparative analysis of the liver transcriptome in the red-eared slider Trachemys scripta elegans under chronic salinity stress." PeerJ 7 (March 21, 2019): e6538. http://dx.doi.org/10.7717/peerj.6538.
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The red-eared slider (Trachemys scripta elegans), identified as one of the 100 most invasive species in the world, is a freshwater turtle originally from the eastern United States and northeastern Mexico. Field investigations have shown that T. s. elegans can survive and lay eggs in saline habitats. In order to understand the molecular mechanisms of salinity adaptation, high-throughput RNA-Seq was utilized to identify the changes in gene expression profiles in the liver of T. s. elegans in response to elevated salinity. We exposed individuals to 0, 5, or 15 psu (practical salinity units) for 30 days. A total of 157.21 million reads were obtained and assembled into 205138 unigenes with an average length of 620 bp and N50 of 964 bp. Of these, 1019 DEGs (differentially expressed genes) were found in the comparison of 0 vs. 5 psu, 1194 DEGs in 0 vs. 15 psu and 1180 DEGs in 5 vs. 15 psu, which are mainly related to macromolecule metabolic process, ion transport, oxidoreductase activity and generation of precursor metabolites and energy by GO (Gene Ontology) enrichment analyses. T. s. elegans can adapt itself into salinity by balancing the entry of sodium and chloride ions via the up-regulation expression genes of ion transport (potassium voltage-gated channel subfamily H member 5, KCNH5; erine/threonine-protein kinase 32, STK32; salt-inducible kinase 1, SIK1; adiponectin, ACDC), and by accumulating plasma urea and free amino acid via the up-regulation expression genes of amino acid metabolism (ornithine decarboxylase antizyme 3, OAZ3; glutamine synthetase, GLUL; asparaginase-like protein 1b, ASRGL; L-amino-acid oxidase-like, LAAO; sodium-dependent neutral amino acid transporter B, SLC6A15s; amino acid permease, SLC7A9) in response to osmotic regulation. An investment of energy to maintain their homeostatic balance is required to salinity adaptation, therefore, the genes related to energy production and conversion (F-ATPase protein 6, ATP6; cytochrome c oxidase subunit I, COX1; cytochrome c oxidase subunit III, COX3; cytochrome b, CYTb; cytochrome P450 17A1, CYP17A1) were up-regulated with the increase of gene expression associated with lipid metabolism (apolipoprotein E precursor, APoE; coenzyme Q-binding protein, CoQ10; high-density lipoprotein particle, SAA) and carbohydrate metabolism (HK, MIP). These findings improve our understanding of the underlying molecular mechanisms involved in salinity adaptation and provide general guidance to illuminate the invasion potential of T. s. elegans into saline environments.
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De Beer, Maria C., Myung-Hee Kim, Joanne M. Wroblewski, Richard C. Charnigo, Ailing Ji, Nancy R. Webb, Frederick C. De Beer, and Deneys R. Van der Westhuyzen. "Abstract 388: Impact of Individual Acute Phase Serum Amyloid A Isoforms on HDL Metabolism in Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 36, suppl_1 (May 2016). http://dx.doi.org/10.1161/atvb.36.suppl_1.388.
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The acute phase reactant serum amyloid A (SAA) is an HDL apolipoprotein that exhibits biological activities as a pro-inflammatory mediator, but its physiological function(s) are poorly understood. Possible functional differences between SAA1.1 and SAA2.1, the two major SAA isoforms, are also unclear. Mice deficient in either SAA1.1 or SAA2.1 were used to investigate SAA isoform plasma clearance rates and effects on HDL structure, composition and apolipoprotein catabolism. The absence of either isoform did not affect the size of the normally enlarged HDL found in acute phase wild type mice, and did not result in significant changes in HDL lipid composition. Plasma clearance rates of normal and acute phase HDL apolipoproteins were determined using native HDL particles. The fractional clearance rates (FCR’s) of apoA-I, apoA-II and SAA were distinct, indicating that neither normal nor acute phase particles are cleared as intact particles. No significant difference was found between the FCR’s of SAA1.1 and SAA2.1 in acute phase mice, suggesting that the selective deposition of SAA1.1 observed in amyloid plaques is not associated with a difference in the rates of plasma clearance of the isoforms. In the absence of the HDL receptor SR-BI, the clearance rate of SAA was reduced by about 30% and remained significantly greater compared to that of apoA-I and apoA-II, indicating a relatively minor role of SR-BI in SAA clearance. These studies contribute to our understanding of the metabolism of SAA and its effects on acute phase HDL composition and catabolism.
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Ji, Ailing, Akinwunmi Akinmusire, Maria C. de Beer, Frederick C. de Beer, Nancy R. Webb, and Deneys R. van der Westhuyzen. "Abstract 380: SAA Lipidation and Delipidation by Hepatocytes." Arteriosclerosis, Thrombosis, and Vascular Biology 37, suppl_1 (May 2017). http://dx.doi.org/10.1161/atvb.37.suppl_1.380.
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Serum amyloid A (SAA) is one of the most striking acute phase reactants that can rapidly increase 1000-fold in plasma concentration in response to inflammatory cytokines. SAA in lipid-free form exhibits pro-inflammatory activities, but its putative physiological function(s) are poorly understood. SAA is produced and secreted largely by the liver and is present in plasma mainly as an HDL apolipoprotein. The pathways by which SAA is lipidated and incorporated into HDL are poorly understood. Plasma SAA is cleared more rapidly than the other major HDL apolipoproteins, but pathways involved in its delipidation and plasma clearance have also not been defined. In this study we examined how SAA is lipidated in primary hepatocytes and how such lipidation relates to the formation of nascent HDL particles. Endogenous hepatocyte SAA was lipidated and released from cells as large particles that were distinct from apoA-I-containing nascent HDL’s. Unlike apoA-I, formation of these SAA-containing particles was independent of ABCA-I. Similarly, when SAA was exogenously added to cells, SAA was lipidated to form nascent particles that were distinct from apoA-I-containing particles. We further studied the interaction of lipid-free and HDL-bound SAA with hepatocytes. Both in lipid-free form and as part of HDL, SAA exhibited significantly greater binding to cells than apoA-I or apoA-II. Binding studies were also carried out with normal and acute phase HDL’s isolated from control and SAA-deficient mice. Together, the results suggested that SAA, unlike apoA-I, is selectively removed from HDL by binding to hepatocytes. These findings may provide new insights into SAA metabolism and function.
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Yalcinkaya, Ahmet, Selma Unal, and Yesim Oztas. "Altered HDL particle in sickle cell disease: decreased cholesterol content is associated with hemolysis, whereas decreased Apolipoprotein A1 is linked to inflammation." Lipids in Health and Disease 18, no. 1 (December 2019). http://dx.doi.org/10.1186/s12944-019-1174-5.
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Abstract Background Hypocholesterolemia is the most frequently encountered lipid abnormality in sickle cell disease (SCD). We enrolled pediatric patients to determine the relationships between lipid profile and parameters of hemolysis, oxidative stress and chronic inflammation in SCD. Methods The study involved 35 pediatric SCD patients and 19 healthy controls. Patients were crisis-free and had not received transfusions for the last 3 months. Total cholesterol, triglyceride, HDL-C, LDL-C, VLDL-C, apolipoprotein A1, apolipoprotein B, LCAT, LDH, bilirubin, haptoglobin, iron, ferritin, hemin, serum amyloid A (SAA), myeloperoxidase (MPO), uric acid, ALT and GGT levels were evaluated in patients’ blood. Results Patients had hypocholesterolemia depicted by lower levels of total cholesterol, HDL-C, LDL-C, as well as Apolipoprotein A1 and Apolipoprotein B compared to controls. The chronic hemolysis of SCD was evident in patients by higher LDH and bilirubin and almost undetectable haptoglobin levels. Hemin levels (as a measure of oxidized heme) were significantly increased in patients with SCD. Inflammation markers, SAA and MPO, were significantly increased in the patients as well. There were negative correlations between HDL-C and LDH, and Apo A1 and SAA. Hemin was positively correlated to MPO. Conclusion Hemolysis was associated with decreased HDL –C, and Inflammation was linked to decreased apolipoprotein A1 levels in our SCD patients. Therefore, we suggest that the HDL particle is altered during the course of the disease. The altered HDL in SCD may become dysfunctional and result with a slowing down of the reverse cholesterol transport.
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Sato, Megumi, Ryunosuke Ohkawa, Akira Yoshimoto, Kouji Yano, Naoya Ichimura, Madoka Nishimori, Shigeo Okubo, Yutaka Yatomi, and Minoru Tozuka. "Effects of serum amyloid A on the structure and antioxidant ability of high-density lipoprotein." Bioscience Reports 36, no. 4 (August 1, 2016). http://dx.doi.org/10.1042/bsr20160075.
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Serum amyloid A (SAA) levels increase during acute and chronic inflammation and are mainly associated with high-density lipoprotein (HDL). In the present study, we investigated the effect of SAA on the composition, surface charge, particle size and antioxidant ability of HDL using recombinant human SAA (rhSAA) and HDL samples from patients with inflammation. We confirmed that rhSAA bound to HDL3 and released apolipoprotein A-I (apoA-I) from HDL without an apparent change in particle size. Forty-one patients were stratified into three groups based on serum SAA concentrations: Low (SAA ≤ 8 μg/ml), Middle (8 < SAA ≤ 100 μg/ml) and High (SAA > 100 μg/ml). The ratios of apoA-I to total protein mass, relative cholesterol content and negative charge of HDL samples obtained from patients with high SAA levels were lower than that for samples from patients with low SAA levels. Various particle sizes of HDL were observed in three groups regardless of serum SAA levels. Antioxidant ability of rhSAA, evaluated as the effect on the formation of conjugated diene in low-density lipoprotein (LDL) induced by oxidation using copper sulfate, was higher than that of apoA-I. Consistent with this result, reconstituted SAA-containing HDL (SAA-HDL) indicated higher antioxidant ability compared with normal HDL. Furthermore, HDL samples obtained from High SAA group patients also showed the highest antioxidant ability among the three groups. Consequently, SAA affects the composition and surface charge of HDL by displacement of apoA-I and enhances its antioxidant ability.