Affinage

Showing SAA1 — SAA is a alias.

SAA1

Serum amyloid A-1 protein · UniProt P0DJI8

Length
122 aa
Mass
13.5 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SAA1 is an acute-phase apolipoprotein that circulates bound to high-density lipoprotein HDL3, where it associates with ApoA-I and ApoA-II and remodels HDL toward larger, phospholipid-depleted, triglyceride-enriched particles (PMID:198813, PMID:4086942, PMID:10845870, PMID:27105909). Its hepatic synthesis is directly induced by the cytokine IL-1 and is secreted through the classical secretory pathway, while the gene family shows tissue-specific expression with distinct hepatic versus macrophage compartments (PMID:6807176, PMID:3680951). SAA1 bioactivity is governed by its lipidation state: lipid-free SAA1 engages cell-surface receptors to drive pro-inflammatory signaling, whereas HDL association neutralizes or counter-regulates most of these effects (PMID:20075072, PMID:23165195, PMID:27898742). The scavenger receptors CD36 and SR-BII mediate SAA1 uptake and trigger JNK, ERK1/2, and p38 MAPK signaling with downstream cytokine/chemokine output, and SAA1 also signals through TLR2 to recruit and activate hepatic stellate cells (via PI3K/Rac/MLC phosphorylation), platelets, and to impair insulin signaling through NF-κB-dependent mechanisms (PMID:20075072, PMID:28423002, PMID:34113824, PMID:33813276, PMID:31060494). A rigorous re-purification study established that much of the cytokine-inducing, ROS-generating, and macrophage-differentiating activity attributed to recombinant SAA1 reflected bacterial contaminants, while genuine SAA1 retains FPR2-dependent leukocyte recruitment and synergy with chemokines such as CXCL8 and CCL3 — an activity mediated by intact protein rather than C-terminal fragments (PMID:32477346, PMID:29371208). Distinct from its inflammatory signaling, the SAA1.1 isoform is intrinsically fibrillogenic and amyloidogenic in vitro and in vivo, and mast cell tryptase cleaves SAA1 to release a highly amyloidogenic N-terminal fragment, defining SAA1 as the precursor of AA amyloidosis; a promoter mutation that doubles SAA1 expression causes autosomal dominant hereditary amyloid A amyloidosis (PMID:11140693, PMID:16483749, PMID:34560138). SAA1 transcription is controlled combinatorially by STAT3, glucocorticoid receptor (in a tissue-specific manner), enhancer acetylation, and the circadian Rev-erbα–C/EBPβ axis downstream of BMAL1 (PMID:12938239, PMID:34597680, PMID:33284950, PMID:38297162). Isoform-specific functions extend to angiogenesis suppression, where SAA1.1 and SAA1.3 (but not SAA1.5) bind αVβ3 integrin to block endothelial adhesion and induce apoptosis (PMID:24608426).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1977 High

    Established the fundamental biochemical identity of SAA as an HDL-associated apolipoprotein rather than a free serum protein, defining the lipoprotein context for all later function.

    Evidence Ultracentrifugation and density gradient fractionation of human serum with immunochemical analysis

    PMID:198813 PMID:301900

    Open questions at the time
    • Did not resolve which HDL apolipoproteins SAA contacts directly
    • No functional consequence of HDL binding established
  2. 1982 Medium

    Identified the liver as a direct cytokine target for SAA induction, explaining the acute-phase rise in SAA during inflammation.

    Evidence In vitro mouse hepatocyte culture with purified leukocytic pyrogen (IL-1), immunoprecipitation, and cell-free translation

    PMID:6807176

    Open questions at the time
    • Did not define transcription factors transducing the IL-1 signal
    • Single inducer tested
  3. 1985 High

    Showed SAA enrichment causally remodels HDL particle composition and size, demonstrating that SAA is not a passive passenger but alters lipoprotein structure.

    Evidence Biophysical fractionation plus in vitro HDL-SAA reconstitution

    PMID:4086942

    Open questions at the time
    • Functional consequence of altered HDL for inflammation or lipid transport not tested
  4. 1987 Medium

    Revealed tissue-specific and isoform-specific expression of the SAA gene family, distinguishing hepatic SAA1/SAA2 from macrophage SAA3 and linking expression shifts to amyloidosis.

    Evidence Comparative mRNA expression across mouse tissues in acute-phase and amyloidosis models

    PMID:3680951

    Open questions at the time
    • mRNA-level only
    • Does not address human SAA1 isoform specifics
  5. 1993 High

    Defined SAA1 protein polymorphisms and common N-terminal post-translational processing, providing the molecular basis for later isoform-specific functional differences.

    Evidence Multiple orthogonal mass spectrometry methods and amino acid analysis

    PMID:8512321

    Open questions at the time
    • Functional consequences of the polymorphisms not addressed
    • No link to amyloidogenicity at this stage
  6. 2000 High

    Demonstrated that amyloidogenicity is an intrinsic structural property of the SAA1.1 isoform, separating fibril-forming from non-fibril-forming SAA variants.

    Evidence Recombinant fibril formation assays plus adenoviral in vivo expression and amyloid induction in mice

    PMID:10845870 PMID:11140693

    Open questions at the time
    • Did not identify cellular proteases or cofactors that initiate fibrillogenesis in vivo
    • Mechanism distinguishing fibril-prone from resistant isoforms structurally undefined
  7. 2006 High

    Linked mast cell biology to amyloidosis by showing tryptase cleaves SAA into an amyloidogenic N-terminal fragment, defining a proteolytic route to fibril precursors.

    Evidence HMC-1 mast cell culture, protease cleavage assays, LC-MS fragment identification, and electron microscopy of protofibrils

    PMID:16483749

    Open questions at the time
    • In vivo relevance of mast-cell-generated fragments to human amyloidosis not established
    • Cytokine readouts may reflect impure preparations
  8. 2010 High

    Identified CD36 as a functional SAA receptor coupling SAA uptake to JNK/ERK MAPK-driven cytokine production, and showed HDL association neutralizes signaling.

    Evidence CD36 overexpression and knockout cells, uptake and cytokine assays, MAPK phosphorylation, and blocking peptides

    PMID:20075072

    Open questions at the time
    • Cytokine effects later complicated by contaminant concerns in rSAA
    • Relative contribution of CD36 versus other receptors in vivo unresolved
  9. 2012 Medium

    Established that lipidation state determines SAA signaling, with lipid-poor but not HDL-bound SAA activating TLR2, while questioning the in vivo physiological cytokine role.

    Evidence J774 macrophage stimulation with lipid-poor versus HDL-associated SAA, TLR2 neutralizing antibodies, and adenoviral expression in SAA-deficient mice

    PMID:23165195

    Open questions at the time
    • In vivo cytokine induction not reproduced
    • Did not exclude preparation contaminants
  10. 2014 Medium

    Defined two non-redundant SAA1 activities: receptor-driven macrophage differentiation downstream of CSF-1R/FPR2, and isoform-specific anti-angiogenesis via αVβ3 integrin binding.

    Evidence Monocyte differentiation with FPR2 and CSF-1R inhibitors plus airway model; isoform restoration in NPC cells with integrin binding and endothelial apoptosis assays

    PMID:24608426 PMID:24846388

    Open questions at the time
    • Macrophage differentiation activity later attributed partly to contaminants
    • Structural basis of isoform-selective integrin binding undefined
  11. 2016 Medium

    Mapped HDL counter-regulation of SAA inflammatory signaling and resolved the structural proximity of SAA to ApoA-I on the HDL surface.

    Evidence Macrophage HDL counter-regulation assays with TLR4 dependence; chemical crosslinking mass spectrometry of HDL-SAA particles

    PMID:27105909 PMID:27898742

    Open questions at the time
    • Mechanism by which HDL physically blocks receptor engagement not resolved
    • Crosslinking provides proximity but not a high-resolution structure
  12. 2017 High

    Identified SR-BII as a second scavenger-receptor route for SAA uptake and tri-MAPK activation, corroborated by transgenic in vivo inflammatory responses.

    Evidence SR-BII overexpression cells with uptake/cytokine/MAPK assays and hSR-BII transgenic mouse SAA challenge

    PMID:28423002

    Open questions at the time
    • Relative in vivo contribution of SR-BII versus CD36 and TLR2 unresolved
    • Did not address lipidation-state dependence
  13. 2018 High

    Showed that the leukocyte-recruiting function of SAA1 operates chiefly by FPR2-dependent synergy with chemokines, and that C-terminal fragments cannot act alone.

    Evidence Purified natural and synthetic SAA1 fragments, chemotaxis assays, FPR2 desensitization and antagonist blocking, and in vivo neutrophil recruitment

    PMID:29371208

    Open questions at the time
    • Endogenous source of the synergizing fragments in vivo not defined
    • Does not address direct receptor structural engagement
  14. 2020 High

    Resolved long-standing contradictions by demonstrating that purified contaminant-free SAA1 retains FPR2-mediated chemotaxis but lacks most TLR-attributed cytokine, ROS, MMP-9, and differentiation activities, reframing the field's interpretation of SAA1 function.

    Evidence RP-HPLC-purified endotoxin-free rSAA1 across chemotaxis, cytokine, ROS, MMP-9, differentiation, and in vivo recruitment assays

    PMID:32477346

    Open questions at the time
    • Does not exclude that endogenous SAA1 modifications confer additional activities
    • Receptor specificity for surviving activities partially defined
  15. 2021 High

    Expanded SAA1 into a tissue-remodeling and metabolic effector, signaling via TLR2 to drive hepatic stellate cell migration, platelet aggregation, and insulin resistance, with promoter mutation establishing a direct Mendelian amyloidosis link.

    Evidence TLR2 genetic/pharmacological epistasis with MLC and Rac readouts; platelet aggregation assays; SAA1 silencing in HFD mice; STAT3 ChIP and VIMP co-IP; promoter luciferase plus family linkage (LOD>5)

    PMID:31060494 PMID:31216990 PMID:33284950 PMID:33719002 PMID:33813276 PMID:34113824 PMID:34560138 PMID:34597680

    Open questions at the time
    • Multiple downstream pathways shown in distinct single-lab disease models
    • Whether lipidation state modulates these effects often untested
  16. 2022 Medium

    Detailed a receptor-to-metabolism cascade in which SAA1 induces PTEN to inhibit Akt and impair GLUT4-dependent glucose uptake through TLR2/4-NF-κB signaling, with feedforward self-induction.

    Evidence Granulosa cell culture, GLUT4 translocation and glucose uptake assays, PTEN/phospho-Akt western blots, and TLR/NF-κB inhibitor blocking

    PMID:34980155

    Open questions at the time
    • Single cell type and lab
    • In vivo metabolic relevance not established here
  17. 2024 High

    Placed SAA1 under circadian control by showing BMAL1 represses SAA1 via the Rev-erbα–C/EBPβ axis, coupling rhythmic transcription to SAA1-driven inflammasome pyroptosis.

    Evidence Myeloid Bmal1 knockout mice, C/EBPβ ChIP at the Saa1 promoter, Rev-erbα inhibition, and pyroptosis assays

    PMID:38297162

    Open questions at the time
    • Human relevance of myeloid circadian SAA1 regulation untested
    • Receptor mediating pyroptotic SAA1 action not pinned down

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the multiple candidate receptors (FPR2, CD36, SR-BII, TLR2, P2X7, αVβ3) are selected in vivo, and how lipidation state, isoform identity, and proteolytic processing jointly dictate which SAA1 activity dominates in a given tissue.
  • No unified structural model of SAA1-receptor engagement
  • Physiological versus contaminant-driven activities not fully partitioned in vivo
  • Relative receptor usage across tissues undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0048018 receptor ligand activity 4 GO:0005198 structural molecule activity 2 GO:0005215 transporter activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
APOA1APOA2CD36FPR2ITGAV/ITGB3SCARB1TLR2VIMP (SELENOS)
Complex memberships
HDL (HDL3)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1977 SAA protein is physically associated with high density lipoprotein HDL3 in human serum, co-sedimenting at density 1.12–1.21 g/cm3 with apolipoproteins ApoA-I and ApoA-II, and can be dissociated into low molecular weight species (~13,000 Da) under dissociating conditions. Sequential ultracentrifugation, density gradient fractionation, immunochemical analysis Proceedings of the National Academy of Sciences of the United States of America High 198813
1977 Low molecular weight SAA (~12,000 Da) self-aggregates and binds serum albumin but not IgG or Bence Jones proteins, forming ~85,000 Da and ~170,000 Da complexes under physiological conditions. Gel filtration with radiolabeled 125I-SAA, cold competition binding assay Journal of immunology Medium 301900
1982 SAA synthesis in isolated mouse hepatocytes is induced in vitro by purified leukocytic pyrogen (LP/IL-1), demonstrating the liver as the direct target for cytokine-driven SAA production; colchicine treatment blocks SAA secretion and causes intracellular accumulation, indicating secretory pathway dependence. In vitro hepatocyte culture, immunoprecipitation, autoradiography, wheat-germ cell-free translation of hepatic mRNA Annals of the New York Academy of Sciences Medium 6807176
1985 SAA enrichment of HDL particles (up to 87% of HDL apolipoprotein) is associated with phospholipid depletion, increased triglyceride content, and larger particle size (radius 4.5–5.3 nm) at normal HDL3 density; this size-density dissociation was also reproduced by in vitro incubation of normal HDL with SAA. Sequential ultracentrifugation, SDS-PAGE, gradient gel electrophoresis, in vitro HDL-SAA incubation Journal of lipid research High 4086942
1987 Mouse peritoneal macrophages express the SAA3 gene exclusively (not SAA1 or SAA2), while liver co-expresses all three SAA genes; during accelerated amyloidosis, macrophage SAA3 expression increases as hepatic SAA1/SAA2 expression decreases, indicating distinct extrahepatic and tissue-specific regulation of SAA gene family members. Differential gene expression analysis (mRNA), comparative acute-phase induction models in mice Journal of immunology Medium 3680951
1993 SAA1 gamma isoform is characterized by alanines at both residues 52 and 57 (rather than valine at one position), representing a novel polymorphism; N-terminal des-Arg and des-Arg-Ser forms of all SAA1 subsets were identified, indicating common post-translational N-terminal processing. Ion-spray mass spectrometry, LC/fast atom bombardment mass spectrometry, collision-activated dissociation MS, amino acid analysis Archives of biochemistry and biophysics High 8512321
1997 SAA1 (but not ApoA-I) enhances cyclooxygenase metabolite formation (TXA2, PGE2, PGF2α) in calcium ionophore-stimulated human monocytes in a dose-dependent manner; anti-SAA1 peptide (40-63) F(ab)2 fragments showed the proposed Ca2+-binding tetrapeptide (Gly48-Pro49-Gly50-Cys51) is not responsible, and SAA1 does not directly bind Ca2+ ions. In vitro monocyte stimulation, eicosanoid measurement, peptide antibody inhibition, Ca2+ binding assay FEBS letters Medium 9428637
2000 Mouse SAA1.1 is fibrillogenic in vitro and causes amyloid deposition in vivo when expressed via adenoviral vector in CE/J mice, while SAA2.2 (the composite isoform in CE/J mice) cannot form fibrils and does not induce amyloid; mixing SAA2.2 with SAA1.1 does not inhibit SAA1.1 fibrillogenesis, demonstrating that CE/J amyloid resistance is due to structural inability of SAA2.2 to form fibrils. Recombinant protein expression, in vitro fibril formation assay, adenoviral vector-mediated in vivo expression, amyloid induction model Laboratory investigation High 11140693
2000 Transgenic overexpression of acute-phase SAA1.1 at moderate levels did not significantly alter ApoA-I or HDL cholesterol levels, but high-level adenoviral SAA1.1 expression produced ~10% larger HDL particles; constitutive SAA4 expression increased HDL size (~10%), VLDL levels (20-fold), and triglycerides (1.7-fold), indicating isoform-specific effects on lipoprotein metabolism. SAA1.1 transgenic mice with inducible metallothionein promoter, adenoviral vector overexpression, lipoprotein profiling Arteriosclerosis, thrombosis, and vascular biology High 10845870
2003 Glucocorticoids induce SAA1 transcription in KB epithelial cells but not in HepG2 hepatoma cells when administered alone; this glucocorticoid effect on SAA1 in both cell lines is glucocorticoid receptor-dependent, demonstrating tissue-specific and receptor-dependent transcriptional regulation of SAA1. RT-PCR mRNA quantification, glucocorticoid/cytokine treatments, receptor dependency analysis in hepatoma and epithelial cell lines European journal of immunology Medium 12938239
2006 SAA activates human mast cells to produce TNF-α and IL-1β in a dose-dependent manner; mast cell tryptase (but not chymase) cleaves SAA to release a highly amyloidogenic N-terminal fragment; intact mast cells degrade SAA and generate protofibrillar intermediates, implicating mast cells in AA amyloidosis pathogenesis. HMC-1 cell culture with rhSAA, ELISA, gel electrophoresis, LC-MS for degradation products, electron microscopy for protofibril detection Biochimica et biophysica acta High 16483749
2010 CD36, a class B scavenger receptor, functions as an SAA receptor mediating SAA uptake and pro-inflammatory signaling; SAA (but not other apolipoproteins) induces 10–50-fold increase in IL-8 secretion in CD36-overexpressing HEK293 cells; SAA-mediated signaling is primarily through JNK and ERK1/2 MAPK pathways; cd36−/− rat macrophages show 60–75% reduction in SAA-induced cytokine secretion; HDL-associated SAA neutralizes the effect. Stable transfection of CD36 in HeLa/HEK293 cells, fluorescent SAA uptake assay, ELISA for cytokines, MAPK phosphorylation assay, NF-κB/MAPK inhibitor studies, cd36−/− rat macrophages/Kupffer cells, CD36 peptide blocking The Journal of biological chemistry High 20075072
2012 Lipid-poor (recombinant or purified) SAA stimulates pro-inflammatory cytokine (G-CSF) production in mouse J774 macrophages via TLR2, but HDL-associated SAA fails to stimulate cytokine production; in vivo adenoviral expression of mouse SAA in SAA-deficient mice did not elevate G-CSF at peak SAA levels, leaving physiological cytokine-inducing role of SAA in vivo ambiguous. J774 cell stimulation with lipid-poor rSAA and HDL-associated SAA, TLR2/4 neutralizing antibodies, adenoviral SAA expression in SAA-deficient mice, ELISA Cytokine Medium 23165195
2014 SAA promotes differentiation of human monocytes into a distinct CD11c(high)CD11b(high) macrophage phenotype in vitro and in vivo (mouse airway challenge model); ALX/FPR2 antagonist WRW4 reduced IL-6 and IL-1β but not phagocytic activity; blocking CSF-1R signaling reduced CD11c(high)CD11b(high) macrophages by 71% and neutrophilic inflammation by 80%, placing SAA-driven macrophage differentiation downstream of CSF-1R. Human monocyte culture with SAA, FPR2 antagonist (WRW4), CSF-1R inhibitor, BALB/c mouse airway SAA challenge, flow cytometry, ELISA FASEB journal Medium 24846388
2014 SAA1.1 and SAA1.3 isoforms, but not SAA1.5, suppress tumor formation and angiogenesis in nasopharyngeal carcinoma (NPC) cell lines in vitro and in vivo; secreted SAA1.1 and SAA1.3 block cell adhesion and induce apoptosis in vascular endothelial cells; SAA1.5 shows weaker binding affinity to αVβ3 integrin and lacks antiangiogenic/apoptotic function. Restoration of SAA1 isoforms in SAA1-deficient NPC cell lines, tumor formation assays in vitro/in vivo, endothelial cell apoptosis assay, αVβ3 integrin binding assay Oncogene High 24608426
2016 HDL counter-regulates SAA-induced sPLA2-IIE and sPLA2-V expression and secretion in murine macrophages in a dose-dependent manner; HDL also suppresses SAA-induced HMGB1 release, NO production, autophagy activation, and cytokine/chemokine secretion via TLR4-dependent signaling. RAW264.7 and primary macrophage culture, SAA and HDL treatment, ELISA, western blot for sPLA2 isoforms and signaling molecules, TLR4 functional dependence assays PloS one Medium 27898742
2016 Heparin interacts with both ApoA-I and SAA in HDL from inflamed mice, forming complex aggregates; mass spectrometry of crosslinked HDL-SAA particles detected multiple crosslinks between ApoA-I and SAA indicating close proximity (within 25 Å) on the HDL surface. Gel electrophoresis, chemical crosslinking, mass spectrometry of crosslinked peptides Biochemical and biophysical research communications Medium 27105909
2017 SR-BII (splice variant of SR-BI) functions as an SAA receptor mediating SAA uptake (~3-fold increase) and pro-inflammatory IL-8 secretion (~3–3.5-fold increase) in transfected cells; SAA activates ERK1/2, p38, and JNK MAPK pathways via SR-BII; transgenic mice overexpressing hSR-BII showed ~2–5-fold higher inflammatory mediator expression in liver and kidney after SAA injection compared to wild-type. Stable transfection of hSR-BII in HeLa/HEK293 cells, fluorescent SAA uptake assay, ELISA, MAPK phosphorylation assay, transgenic mouse in vivo SAA challenge, histology, plasma transaminase measurement PloS one High 28423002
2018 COOH-terminal SAA1 fragments (SAA1(46-112) bovine; SAA1(47-104) human) fail to directly chemoattract leukocytes, induce chemokines, or stimulate ERK signaling, but potently synergize with CCL3 (monocyte migration) and CXCL8 (neutrophil chemotaxis) via FPR2; SAA1(47-104) desensitizes intact SAA1α/CXCL8 synergy, and WRW4 (FPR2 antagonist) completely blocks synergy, confirming FPR2 as the mediating receptor. Protein purification from bovine serum, chemical synthesis of peptides, chemotaxis assays, ERK signaling assay, FPR2 antagonist (WRW4) blocking, in vivo mouse peritoneal neutrophil recruitment assay Blood High 29371208
2019 SAA1 increases NOX4/ROS production and activates the p38MAPK/NF-κB pathway to promote LPS-induced inflammatory cytokine release (IL-1β, IL-6, IL-8, IL-17, TNF-α, MCP-1) in vascular smooth muscle cells; both SAA1 siRNA and NOX4 siRNA attenuate this pathway, and combined knockdown shows no additive effect, placing SAA1 upstream of NOX4 in this signaling cascade. SAA1 siRNA, NOX4 siRNA, recombinant SAA1 protein treatment, lucigenin-enhanced chemiluminescence for O2− and NADPH oxidase activity, qRT-PCR, western blot for p38MAPK/NF-κB pathway proteins BMC molecular and cell biology Medium 31216990
2019 SAA1/Saa1 silencing inhibits palmitate-induced insulin resistance in Huh7 cells and HFD-induced insulin resistance in mice via suppression of the NF-κB pathway; SAA1 promotes NF-κB p65 nuclear translocation both in vitro and in vivo, linking SAA1 to hepatic insulin signaling impairment. SAA1 siRNA in Huh7 cells, HFD mouse model with Saa1 silencing, NF-κB inhibitor (BAY 11-7082), RT-qPCR, western blot, glucose tolerance test, insulin sensitivity assay, NF-κB p65 nuclear/cytoplasmic fractionation Molecular medicine Medium 31060494
2020 Purified recombinant SAA1 (hrSAA1) free of LPS, lipoprotein, and formylated peptide contaminants retains leukocyte-recruiting capacity in vivo and synergy with other chemoattractants via FPR2, and promotes monocyte survival; however, hrSAA1 lacks most cytokine-inducing, MMP-9 release, ROS generation, and macrophage differentiation activities previously attributed to SAA1, indicating these TLR-mediated effects were due to bacterial contaminants in commercial rSAA1 preparations. RP-HPLC purification of rSAA1, endotoxin removal, chemotaxis assays, cytokine ELISA, MMP-9 measurement, ROS assay, macrophage differentiation, in vivo leukocyte recruitment, FPR2 activation assay Frontiers in immunology High 32477346
2020 SAA1 is synthesized de novo in human placental villous trophoblasts; SAA1 expression increases upon syncytialization and with LPS, TNF-α, and cortisol treatment; SAA1 treatment of syncytiotrophoblasts increases IL-1β, IL-8, TNF-α, COX-2 expression and PGF2α production; intraperitoneal SAA1 injection in mice induces preterm birth and increases inflammatory mediators in placenta. RT-PCR, western blot, immunohistochemistry in human placenta; syncytialization cell model; cytokine ELISA; in vivo SAA1 injection mouse model with preterm birth readout Frontiers in immunology Medium 32582166
2021 SAA1 acts as a hepatic endogenous chemokine for TLR2 on hepatic stellate cells (HSCs), recruiting them toward injury loci; SAA1/TLR2 signaling stimulates Rac GTPases through PI3K-dependent pathways, induces MLC phosphorylation (pSer19), and drives actin filament remodeling and directional migration; genetic TLR2 deletion and pharmacological PI3K inhibition both abolish MLCpSer19 phosphorylation and HSC migration. Gene manipulation (TLR2 knockout, SAA1 overexpression/knockdown) in cell and mouse models, PI3K pharmacological inhibition, MLC phosphorylation western blot, Rac GTPase activity assay, migration assay iScience High 34113824
2021 SAA1 promotes intrahepatic platelet aggregation and liver inflammation in NAFLD; SAA1-treated platelets show increased aggregation sensitivity, activation, and adhesion partly via TLR2 signaling; SAA1 knockdown in vivo reduces intrahepatic platelet aggregation and ameliorates fatty liver inflammation in HFD mice. SAA1 recombinant protein platelet treatment, TLR2 inhibitor blocking, platelet aggregation/activation/adhesion assays, in vivo SAA1 knockdown in HFD mice, liver histology, inflammation markers Biochemical and biophysical research communications Medium 33813276
2021 SAA1 is transcriptionally activated by STAT3 and directly binds VIMP to inhibit the Derlin-1/VCP/VIMP complex, preventing misfolded protein degradation and causing endoplasmic reticulum stress (elevated GRP78), which promotes renal interstitial fibrosis. Bioinformatics prediction confirmed by SAA1 expression in UUO mouse model and TGF-β-induced HK2 cells, STAT3 ChIP/transcriptional activation assays, co-immunoprecipitation of SAA1 with VIMP, ER stress markers (GRP78), siRNA knockdown Experimental cell research Medium 34597680
2021 SAA1 promotes pro-labour inflammatory mediators (IL-8, IL-6, CXCL5, CCL2, ICAM1, ICAM5, COX-2, PGE2) in human primary myometrial cells through activation of the YAP (Yes-associated protein) pathway; SAA1 knockdown reduces phospho-YAP and downstream pro-inflammatory gene expression, while YAP overexpression reverses the knockdown effect. SAA1 siRNA in human primary myometrial cells, YAP overexpression rescue experiment, western blot for pYAP, cytokine/mediator ELISA and RT-PCR Molecular and cellular biochemistry Medium 33719002
2021 A T>C mutation in the SAA1 promoter (chr11:18287683) doubles basal SAA1 promoter activity and causes hereditary amyloid A amyloidosis with autosomal dominant inheritance; the mutation is linked to the amyloidogenic SAA1.1 haplotype, and tocilizumab (anti-IL-6 receptor antibody) has beneficial effects when given early. SAA1 promoter activity assay (luciferase or equivalent), genetic linkage analysis (LOD score >5), SAA level measurement in genetically affected and unaffected family members, amyloid composition analysis Kidney international High 34560138
2021 SAA1 is upregulated in gastric cancer-associated fibroblasts (CAFs) due to increased H3K27ac (active enhancer mark) at the SAA1 promoter and two far upstream enhancer regions; BET bromodomain inhibitors (JQ1 and mivebresib) decrease SAA1 expression and tumor-promoting effects; conditioned medium from SAA1-overexpressing NCAFs increases gastric cancer cell migration comparably to CAF-CM, and CAF-CM tumor promotion is mostly abolished by SAA1 knockdown. ChIP-qPCR for H3K27ac, SAA1 overexpression in NCAFs, SAA1 knockdown in CAFs, conditioned medium migration assay, BET inhibitor treatment Carcinogenesis Medium 33284950
2022 Ovarian granulosa cells produce SAA1, which can induce its own expression (feedforward loop); excessive SAA1 attenuates insulin-stimulated GLUT4 membrane translocation and glucose uptake via induction of PTEN and subsequent inhibition of Akt phosphorylation, effects blocked by TLR2/4 and NF-κB inhibitors. Primary granulosa cell culture, SAA1 treatment, GLUT4 membrane translocation assay, glucose uptake assay, western blot for PTEN and phospho-Akt, TLR2/4 and NF-κB inhibitor blocking experiments Reproductive biology and endocrinology Medium 34980155
2023 SAA1 promotes cancer stem cell transformation and drives type 2 immunity (Th2 polarization) via the P2X7 receptor, restricting anti-tumor immunity and promoting tumor fibrosis; anti-SAA neutralization antibody reverses these effects in patient-derived organoid/PBMC co-culture model. scRNA-seq (public dataset), ex vivo patient-derived organoid/PBMC co-culture, anti-SAA neutralizing antibody, P2X7 receptor inhibition, immune cell polarization assays Cell death & disease Medium 37925492
2024 Circadian clock BMAL1 suppresses SAA1 transcription in myeloid cells via the Rev-erbα-C/EBPβ axis: Rev-erbα (reduced in Bmal1-deficient cells) inhibits C/EBPβ binding to the Saa1 promoter; Bmal1 deficiency enhances C/EBPβ-Saa1 promoter binding and SAA1 expression; SAA1 in turn promotes noncanonical inflammasome-mediated pyroptosis; type 1 IFN receptor signaling is required for IFN-β/poly(I:C)-induced SAA1 production. Myeloid-specific Bmal1 knockout mice, transcriptome analysis, ChIP for C/EBPβ at Saa1 promoter, Rev-erbα inhibitor (SR8278), exogenous SAA1 administration, noncanonical inflammasome pyroptosis assays Experimental & molecular medicine High 38297162

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1977 Amyloid protein SAA is associated with high density lipoprotein from human serum. Proceedings of the National Academy of Sciences of the United States of America 384 198813
1996 Human serum amyloid A (SAA) protein: a prominent acute-phase reactant for clinical practice. European journal of clinical investigation 296 8817153
2016 Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults. Current medicinal chemistry 192 27087246
1993 Serum amyloid A (SAA): an acute phase protein and apolipoprotein. Atherosclerosis 169 7504491
1999 Serum amyloid A (SAA): a concise review of biology, assay methods and clinical usefulness. Clinical chemistry and laboratory medicine 151 10369107
2003 The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis and rheumatism 138 12687559
2020 Serum Amyloid A (SAA) Proteins. Sub-cellular biochemistry 122 32189310
1975 Isolation and characterization of amyloid-related serum protein SAA as a low molecular weight protein. Scandinavian journal of immunology 120 52891
2011 Identification and validation of SAA as a potential lung cancer biomarker and its involvement in metastatic pathogenesis of lung cancer. Journal of proteome research 110 21141971
1985 Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction. Journal of lipid research 104 4086942
1982 The biology of SAA: identification of the inducer, in vitro synthesis, and heterogeneity demonstrated with monoclonal antibodies. Annals of the New York Academy of Sciences 99 6807176
2020 Cancer-associated adipocytes promote pancreatic cancer progression through SAA1 expression. Cancer science 89 32535957
2010 CD36 is a novel serum amyloid A (SAA) receptor mediating SAA binding and SAA-induced signaling in human and rodent cells. The Journal of biological chemistry 89 20075072
2021 High-Density Lipoproteins and Serum Amyloid A (SAA). Current atherosclerosis reports 82 33447953
2010 Polymorphisms in the SAA1/2 gene are associated with carotid intima media thickness in healthy Han Chinese subjects: the Cardiovascular Risk Survey. PloS one 73 21103356
1989 Direct binding enzyme-linked immunosorbent assay (ELISA) for serum amyloid A (SAA). Journal of immunological methods 66 2607146
2012 SAA1 is over-expressed in plasma of non small cell lung cancer patients with poor outcome after treatment with epidermal growth factor receptor tyrosine-kinase inhibitors. Journal of proteomics 64 22771314
1999 Influence of genotypes at SAA1 and SAA2 loci on the development and the length of latent period of secondary AA-amyloidosis in patients with rheumatoid arthritis. Human genetics 59 10543406
1986 Localization of human SAA gene(s) to chromosome 11 and detection of DNA polymorphisms. Biochemical and biophysical research communications 57 3015139
2019 Expression of SAA1, SAA2 and SAA4 genes in human primary monocytes and monocyte-derived macrophages. PloS one 55 31100086
2015 Quantification of SAA1 and SAA2 in lung cancer plasma using the isotype-specific PRM assays. Proteomics 52 26177823
2004 Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC medical genetics 50 15018633
2001 Serum amyloid A protein (SAA) in colorectal carcinoma. Clinical chemistry and laboratory medicine 49 11341746
2014 SAA drives proinflammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 24846388
1987 Differential expression of the amyloid SAA 3 gene in liver and peritoneal macrophages of mice undergoing dissimilar inflammatory episodes. Journal of immunology (Baltimore, Md. : 1950) 45 3680951
2020 Serum Amyloid A1 (SAA1) Revisited: Restricted Leukocyte-Activating Properties of Homogeneous SAA1. Frontiers in immunology 44 32477346
2012 SAA does not induce cytokine production in physiological conditions. Cytokine 44 23165195
2003 Tissue-specific regulation of the human acute-phase serum amyloid A genes, SAA1 and SAA2, by glucocorticoids in hepatic and epithelial cells. European journal of immunology 44 12938239
2001 Relative serum amyloid A (SAA) values: the influence of SAA1 genotypes and corticosteroid treatment in Japanese patients with rheumatoid arthritis. Annals of the rheumatic diseases 42 11156544
2020 Urinary I-FABP, L-FABP, TFF-3, and SAA Can Diagnose and Predict the Disease Course in Necrotizing Enterocolitis at the Early Stage of Disease. Journal of immunology research 39 32190704
2013 Antioxidants inhibit SAA formation and pro-inflammatory cytokine release in a human cell model of alkaptonuria. Rheumatology (Oxford, England) 39 23704321
2009 Serum amyloid A (SAA): a novel biomarker for uterine serous papillary cancer. British journal of cancer 39 19536090
2003 Analysis of the modifying effects of SAA1, SAA2 and TNF-alpha gene polymorphisms on development of amyloidosis in FMF patients. The Turkish journal of pediatrics 38 14696796
2021 Hepatocytes derived increased SAA1 promotes intrahepatic platelet aggregation and aggravates liver inflammation in NAFLD. Biochemical and biophysical research communications 37 33813276
2021 Arecoline induces epithelial-mesenchymal transformation and promotes metastasis of oral cancer by SAA1 expression. Cancer science 36 33626219
2011 Polymorphisms in the SAA1 gene are associated with ankle-to-brachial index in Han Chinese healthy subjects. Blood pressure 34 21449704
2011 Widespread expression of SAA and Hp RNA in bovine tissues after evaluation of suitable reference genes. Veterinary immunology and immunopathology 34 22230385
2004 Influence of Serum Amyloid A (SAA1) and SAA2 gene polymorphisms on renal amyloidosis, and on SAA/C-reactive protein values in patients with familial mediterranean fever in the Turkish population. The Journal of rheumatology 32 15170927
2021 SAA1 is upregulated in gastric cancer-associated fibroblasts possibly by its enhancer activation. Carcinogenesis 30 33284950
2021 The Clinical Diagnostic Values of SAA, PCT, CRP, and IL-6 in Children with Bacterial, Viral, or Co-Infections. International journal of general medicine 30 34729020
2013 Organization and biology of the porcine serum amyloid A (SAA) gene cluster: isoform specific responses to bacterial infection. PloS one 30 24146912
2019 SAA1 increases NOX4/ROS production to promote LPS-induced inflammation in vascular smooth muscle cells through activating p38MAPK/NF-κB pathway. BMC molecular and cell biology 28 31216990
2019 Silencing of SAA1 inhibits palmitate- or high-fat diet induced insulin resistance through suppression of the NF-κB pathway. Molecular medicine (Cambridge, Mass.) 27 31060494
2023 SAA suppresses α-PD-1 induced anti-tumor immunity by driving TH2 polarization in lung adenocarcinoma. Cell death & disease 26 37925492
2019 Apoproteins E, A-I, and SAA in Macrophage Pathobiology Related to Atherogenesis. Frontiers in pharmacology 25 31231209
1977 Serum amyloid A (SAA) protein-interaction with itself and serum albumin. Journal of immunology (Baltimore, Md. : 1950) 25 301900
2021 High SAA1 Expression Predicts Advanced Tumors in Renal Cancer. Frontiers in oncology 24 34084746
2018 COOH-terminal SAA1 peptides fail to induce chemokines but synergize with CXCL8 and CCL3 to recruit leukocytes via FPR2. Blood 24 29371208
2014 SAA1 polymorphisms are associated with variation in antiangiogenic and tumor-suppressive activities in nasopharyngeal carcinoma. Oncogene 24 24608426
2006 Serum amyloid A (SAA) activates human mast cells which leads into degradation of SAA and generation of an amyloidogenic SAA fragment. Biochimica et biophysica acta 24 16483749
1986 Serum amyloid protein A (SAA): an indicator of inflammation in AIDS and AIDS-related complex (ARC). Scandinavian journal of infectious diseases 24 3095915
2020 Expressions of SAA, CRP, and FERR in different severities of COVID-19. European review for medical and pharmacological sciences 23 33215460
2011 Serum amyloid A3 (SAA3), not SAA1 appears to be the major acute phase SAA isoform in the pig. Veterinary immunology and immunopathology 23 21439655
2006 SAA1 gene polymorphisms and the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis. Modern rheumatology 23 17039310
2005 Distribution of saa gene variants in verocytotoxigenic Escherichia coli isolated from cattle and food. Research in microbiology 23 16171978
2000 Expression of mouse acute-phase (SAA1.1) and constitutive (SAA4) serum amyloid A isotypes: influence on lipoprotein profiles. Arteriosclerosis, thrombosis, and vascular biology 23 10845870
2016 High-Density Lipoprotein (HDL) Counter-Regulates Serum Amyloid A (SAA)-Induced sPLA2-IIE and sPLA2-V Expression in Macrophages. PloS one 22 27898742
2013 The contribution of SAA1 polymorphisms to Familial Mediterranean fever susceptibility in the Japanese population. PloS one 22 23437051
2020 SAA (Serum Amyloid A): A Novel Predictor of Stroke-Associated Infections. Stroke 21 33161846
2021 A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis. Kidney international 20 34560138
2000 Expression of mouse apolipoprotein SAA1.1 in CE/J mice: isoform-specific effects on amyloidogenesis. Laboratory investigation; a journal of technical methods and pathology 20 11140693
1993 A novel polymorphism of human serum amyloid A protein, SAA1 gamma, is characterized by alanines at both residues 52 and 57. Archives of biochemistry and biophysics 20 8512321
1981 Enzyme-linked immunosorbent assay of serum protein SAA in rhesus monkeys with secondary amyloidosis. Laboratory investigation; a journal of technical methods and pathology 20 7253566
2023 Enteric fungi protect against intestinal ischemia-reperfusion injury via inhibiting the SAA1-GSDMD pathway. Journal of advanced research 19 37717911
2022 Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis-Induced Lung Injury in Mice via Exosomal SAA1. Molecular pharmaceutics 19 36173129
2021 SAA and CRP are potential indicators in distinction and severity assessment for children with influenza. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 19 34052408
2021 SAA1 is transcriptionally activated by STAT3 and accelerates renal interstitial fibrosis by inducing endoplasmic reticulum stress. Experimental cell research 19 34597680
2020 De novo Synthesis of SAA1 in the Placenta Participates in Parturition. Frontiers in immunology 19 32582166
2017 Human SR-BII mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo. PloS one 19 28423002
1985 Serum amyloid A protein (SAA) subtypes in acute and chronic inflammatory conditions. Annals of the rheumatic diseases 19 3931569
2023 Acute-serum amyloid A and A-SAA-derived peptides as formyl peptide receptor (FPR) 2 ligands. Frontiers in endocrinology 18 36817589
1985 Amyloid-related serum protein (SAA) during and after pregnancy in healthy women and women with rheumatic disease. Acta pathologica, microbiologica, et immunologica Scandinavica. Section C, Immunology 17 3984747
2021 SAA1 knockdown promotes the apoptosis of glioblastoma cells via downregulation of AKT signaling. Journal of Cancer 16 33854635
1997 Serum amyloid A (SAA) protein enhances formation of cyclooxygenase metabolites of activated human monocytes. FEBS letters 16 9428637
2018 Serum amyloid A1 (SAA1) gene polymorphisms in Japanese patients with adult-onset Still's disease. Medicine 15 30544414
2024 Deficiency of circadian clock gene Bmal1 exacerbates noncanonical inflammasome-mediated pyroptosis and lethality via Rev-erbα-C/EBPβ-SAA1 axis. Experimental & molecular medicine 14 38297162
2021 SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury. iScience 14 34113824
1999 Expression of recombinant feline serum amyloid A (SAA) protein. The Journal of veterinary medical science 14 10487231
1979 Serum amyloid protein SAA, C-reactive protein and lysozyme in leprosy. International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association 14 572349
2023 HDL anti-inflammatory function is impaired and associated with high SAA1 and low APOA4 levels in aneurysmal subarachnoid hemorrhage. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 13 37357772
2021 Baseline and early changes in circulating Serum Amyloid A (SAA) predict survival outcomes in advanced non-small cell lung cancer patients treated with Anti-PD-1/PD-L1 monotherapy. Lung cancer (Amsterdam, Netherlands) 13 34087538
2020 MFGE8, ALB, APOB, APOE, SAA1, A2M, and C3 as Novel Biomarkers for Stress Cardiomyopathy. Cardiovascular therapeutics 13 32695227
2020 LINC00160 mediates sunitinib resistance in renal cell carcinoma via SAA1 that is implicated in STAT3 activation and compound transportation. Aging 13 32921632
1999 CpG-DNA upregulates the major acute-phase proteins SAA and SAP. Cellular microbiology 13 11207541
2022 Elevated SAA1 promotes the development of insulin resistance in ovarian granulosa cells in polycystic ovary syndrome. Reproductive biology and endocrinology : RB&E 12 34980155
2022 Serum Proteomic Analysis Identifies SAA1, FGA, SAP, and CETP as New Biomarkers for Eosinophilic Granulomatosis With Polyangiitis. Frontiers in immunology 12 35757752
2021 SAA1 regulates pro-labour mediators in term labour by activating YAP pathway. Molecular and cellular biochemistry 12 33719002
2020 Serum Amyloid A (SAA) Concentration after Vaccination in Horses and Mules. Journal of equine veterinary science 12 32797788
2018 The ectoenzyme-side of matrix metalloproteinases (MMPs) makes inflammation by serum amyloid A (SAA) and chemokines go round. Immunology letters 12 29870759
2016 Heparin interactions with apoA1 and SAA in inflammation-associated HDL. Biochemical and biophysical research communications 12 27105909
2023 SAA1 deficiency alleviates cardiac remodeling by inhibiting NF-κB/p38/JNK and TGFβ/Smad pathways. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 37022639
2018 Serum amyloid A1 (SAA1) protein in human colostrum. FEBS open bio 11 29511620
1991 Characterization of an isoelectric focusing variant of SAA1 (ASP-72) in a family of Turkish origin. Biochemical and biophysical research communications 11 1764061
2024 SAA1-dependent reprogramming of adipocytes by tumor cells is associated with triple negative breast cancer aggressiveness. International journal of cancer 10 38289016
2024 Sodium oligomannate disrupts the adherence of Ribhigh bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice. Cell discovery 10 39557828
2013 Associations of SAA1 gene polymorphism with lipid lelvels and osteoporosis in Chinese women. Lipids in health and disease 10 23522429
1990 apo-SAA1/apo-SAA2 isotype ratios during casein- and amyloid-enhancing-factor-induced secondary amyloidosis in A/J and C57BL/6J mice mice. Scandinavian journal of immunology 10 2309099
2023 Identification of SAA1 as a novel metastasis marker in ovarian cancer and development of a graphene-based detection platform for early assessment. Journal of cancer research and clinical oncology 9 37707574
2021 Relationship Between Serum Amyloid A1 (SAA1) Gene Polymorphisms Studies with Obesity in the Saudi Population. Diabetes, metabolic syndrome and obesity : targets and therapy 9 33688224
2016 CRP and SAA1 Haplotypes Are Associated with Both C-Reactive Protein and Serum Amyloid A Levels: Role of Suppression Effects. Mediators of inflammation 9 27313400

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