Disease relevance of Saa1

• In addition, colchicine, currently used for the treatment of amyloidosis, blocks the secretion of SAA from the hepatocyte, as has been shown for another acute phase reactan, C-reactive protein [1].
• Hepatic catabolism of serum amyloid A during an acute phase response and chronic inflammation [2].
• To establish a possible link between these two events, we have carried out partial N-terminal sequence analysis of affinity purified SAA derivatives from peritoneal macrophages isolated at 4 weeks post-infection from alveolar hydatid cyst infected C57BL/6 mice [3].
• RESULTS: Atorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti-type II collagen IgG production), and biochemical (interleukin-6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity [4].
• Protective effects of alpha1-acid glycoprotein and serum amyloid A on concanavalin A-induced liver failure via interleukin-6 induction by ME3738 [5].

High impact information on Saa1

• Monokine-induced synthesis of serum amyloid A protein by hepatocytes [1].
• The site of synthesis of SAA has been controversial, with previous evidence suggesting that AA related proteins arise in liver, connective tissues, polymorphonuclear neutrophil leukocytes and spleen [1].
• Diverse gene expression for isotypes of murine serum amyloid A protein during acute phase reaction [6].
• All susceptible strains of mice described to date codominantly express two serum amyloid A (apoSAA) isoforms, apoSAA1 and apoSAA2, of which only apoSAA2 serves as a precursor for amyloid fibrils [7].
• Expression of the third member of the serum amyloid A gene family in mouse adipocytes [8].

Chemical compound and disease context of Saa1

• Mucosal production of complement C3 and serum amyloid A is differentially regulated in different parts of the gastrointestinal tract during endotoxemia in mice [9].
• CONCLUSION; Fenofibrate inhibits experimental amyloidosis by reducing levels of the precursor SAA [10].
• A homology search of the sequence of clone 6.9 revealed it to encode a cDNA to serum amyloid A protein; consistent with this identification, expression of 6.9 mRNA was highly induced in both kidney and liver after treatment of mice with Escherichia coli lipopolysaccharide [11].
• Our findings integrate previous isolated observations about SAA into the sphere of cholesterol transport, establish a function for a major acute-phase protein, and offer a novel approach to mobilizing macrophage cholesterol at sites of atherogenesis [12].
• In experimental murine inflammation-associated amyloidosis (AA amyloidosis), an interaction between heparan sulfate and serum amyloid A (SAA), the AA precursor, has been demonstrated and is believed to play an important role in AA amyloidogenesis [13].

Biological context of Saa1

• Our results suggest that SAF is a key regulator of cytokine-mediated SAA gene expression in some nonhepatic cells [14].
• Transfection and DNA-binding studies were performed to investigate the mechanism controlling cytokine-induced, nonhepatic expression of the SAA gene [14].
• In order to explore the mechanism of SAA isotype-specific amyloid protein AA deposition, the molecular kinetics of the serum amyloid proteins were examined in CBA mice during casein induction of amyloidosis [15].
• The serum amyloid A (SAA) proteins make up a multigene family of apolipoproteins associated with high density lipoproteins [16].
• Starting with induced liver RNA, we have constructed a recombinant plasmid containing most of the DNA sequence encoding the serum amyloid A polypeptide [17].

Anatomical context of Saa1

• These results indicate that fibronectin plays an important role in the development of amyloidosis by working as a linking protein between SAA and the cell surface of macrophages [18].
• Extrahepatic SAA1 and SAA2 mRNA were induced by lipopolysaccharide in kidney proximal and distal convoluted tubule epithelia, and SAA1 mRNA was induced in epithelial lining the mucosa of the ileum and large intestine, indicating that there may be more than one function for the apoSAA gene family related to site of and stimulus for expression [19].
• Induction of serum amyloid A inflammatory response genes in irradiated bone marrow cells [20].
• The small intestine, primarily the ileum, and the large intestine of unstimulated control animals contained 5- and 15-fold higher SAA mRNA levels than control liver [21].
• Adrenal gland expressed SAA mRNA at a low level (0.5% of hepatic level), and was the only extrahepatic tissue with elevated SAA mRNA after casein injection [21].

Associations of Saa1 with chemical compounds

• Kinetics of SAA protein distribution and gene expression after acute phase stimulation by casein or lipopolysaccharide were examined using immunocytochemistry for protein and RNA blot and in situ hybridization with probes for SAA1 and SAA2 mRNA [19].
• Centrally administered anti-Fas (1 microg/mouse, i.c.v.) induced elevated levels of corticosterone, IL-6, and SAA comparable to those observed after i.c.v. administration of recombinant murine TNF [22].
• During the preamyloidotic phase, pepstatin-treated mice had higher concentrations of SAA in serum and spleen than control mice [23].
• As found for rat and human liver cells, mouse hepatocytes responded to the cytokines by increasing production of acute-phase proteins, which in mice include haptoglobin, alpha 1-acid glycoprotein, complement C-3, serum amyloid A, and hemopexin [24].
• We examined the effects of glucocorticoids (GC) on serum amyloid A (SAA) mRNA expression using an antisense SAA3 probe, and found that dexamethasone (DEX) and triamcinolone (TC) increased SAA3 mRNA expression by macrophage cell lines in a time- and concentration-dependent manner [25].

Regulatory relationships of Saa1

• This suggested that suppression of SAA levels was not the primary event inhibiting amyloid deposition [26].
• METHODS AND RESULTS: A cytokine mixture (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and IL-6) simultaneously induced SAA and repressed apoA-I and PON-1 expression levels [27].
• The injection of IL-2 induced SAA gene expression in the liver [28].
• Only liposomes containing intact SAA2.1 or its residues 1-20 or 74-103 promoted the efflux of cholesterol in vivo [29].
• Epithelial induction of serum amyloid A is possibly relevant to mucosal inflammation because that was observed in bacteria-reconstituted and dextran sulfate sodium-induced colitis in vivo and because interleukin-beta and lipopolysaccharide induced its mRNA in vitro [30].

Other interactions of Saa1

• Generation and use of site-specific antibodies to serum amyloid A for probing amyloid A development [31].
• On the other hand, administration of murine NGF did not elevate serum corticosterone or IL-6, but induced SAA [22].
• As D-GalN sensitizes the host for the toxic effects of TNF-alpha, a possible mechanism could be the prevention of synthesis of the major acute-phase proteins SAA and SAP [32].
• During the acute-phase reaction, genes encoding CP, SAA, AGP, and HP demonstrate unique extrahepatic tissue specific patterns of expression in kidney, spleen, thymus, heart, brain, lung, testis, and epididymis [33].
• SAA mRNA levels were lower in the remaining tissues and ranged from 0.1% in the brain and pancreas to 1.0% in the small intestine, with the ileum containing 50-fold more than the duodenum [21].

Analytical, diagnostic and therapeutic context of Saa1

• By indirect immunofluorescence using anti-SAA/AA antibodies the initial deposition of SAA/AA was recognized in the marginal zone of spleen at 20 days after azocasein injection [18].
• Immunoelectron microscopy using anti-SAA/AA revealed the presence of positively stained flocculent materials on cell surfaces of macrophages in the marginal area in addition to amyloid fibril [18].
• Binding assay of SAA on frozen sections revealed the presence of SAA-binding substances in the perifollicular area [18].
• Circular-dichroism studies on two murine serum amyloid A proteins [34].
• Livers from animals receiving 14 daily injections of casein were 31% less active than control livers at degrading SAA (8.1 +/- 1.6%/g/3 hr for treated group vs. 11.7 +/- 2.3%/g/3 hr for control group, P less than 0.025) [2].

References