High-Density Lipoproteins and Serum Amyloid A (SAA)

Abstract Purpose of Review Serum amyloid A (SAA) is a highly sensitive acute phase reactant that has been linked to a number of chronic inflammatory diseases. During a systemic inflammatory response, liver-derived SAA is primarily found on high-density lipoprotein (HDL). The purpose of this review is to discuss recent literature addressing the pathophysiological functions of SAA and the significance of its association with HDL. Recent Findings Studies in gene-targeted mice establish that SAA contributes to atherosclerosis and some metastatic cancers. Accumulating evidence indicates that the lipidation state of SAA profoundly affects its bioactivities, with lipid-poor, but not HDL-associated, SAA capable of inducing inflammatory responses in vitro and in vivo. Factors that modulate the equilibrium between lipid-free and HDL-associated SAA have been identified. Summary HDL may serve to limit SAA’s bioactivities in vivo. Understanding the factors leading to the release of systemic SAA from HDL may provide insights into chronic disease mechanisms.

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Serum amyloid A induces G-CSF expression and neutrophilia via Toll-like receptor 2

Blood ◽

10.1182/blood-2008-03-139923 ◽

2009 ◽

Vol 113 (2) ◽

pp. 429-437 ◽

Cited By ~ 109

Author(s):

Rong L. He ◽

Jian Zhou ◽

Crystal Z. Hanson ◽

Jia Chen ◽

Ni Cheng ◽

...

Keyword(s):

Serum Amyloid A ◽

Inflammatory Diseases ◽

Serum Amyloid ◽

Proteinase K ◽

In Vivo Studies ◽

Toll Like Receptor ◽

Amyloid A ◽

Toll Like Receptor 2

Abstract The acute-phase protein serum amyloid A (SAA) is commonly considered a marker for inflammatory diseases; however, its precise role in inflammation and infection, which often result in neutrophilia, remains ambiguous. In this study, we demonstrate that SAA is a potent endogenous stimulator of granulocyte colony-stimulated factor (G-CSF), a principal cytokine-regulating granulocytosis. This effect of SAA is dependent on Toll-like receptor 2 (TLR2). Our data demonstrate that, in mouse macrophages, both G-CSF mRNA and protein were significantly increased after SAA stimulation. The induction of G-CSF was blocked by an anti-TLR2 antibody and markedly decreased in the TLR2-deficient macrophages. SAA stimulation results in the activation of nuclear factor–κB and binding activity to the CK-1 element of the G-CSF promoter region. In vitro reconstitution experiments also support that TLR2 mediates SAA-induced G-CSF expression. In addition, SAA-induced secretion of G-CSF was sensitive to heat and proteinase K treatment, yet insensitive to polymyxin B treatment, indicating that the induction is a direct effect of SAA. Finally, our in vivo studies confirmed that SAA treatment results in a significant increase in plasma G-CSF and neutrophilia, whereas these responses are ablated in G-CSF– or TLR2-deficient mice.

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Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)67562-3 ◽

1986 ◽

Vol 261 (21) ◽

pp. 9644-9651 ◽

Cited By ~ 12

Author(s):

G A Coetzee ◽

A F Strachan ◽

D R van der Westhuyzen ◽

H C Hoppe ◽

M S Jeenah ◽

...

Keyword(s):

High Density Lipoprotein ◽

Serum Amyloid A ◽

Density Lipoprotein ◽

High Density ◽

Serum Amyloid ◽

Amyloid A ◽

Human High Density Lipoprotein

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Evidence for the role of high density lipoproteins in mediating the antioxidant effect of estrogens

Acta Endocrinologica ◽

10.1530/eje.0.1420079 ◽

2000 ◽

pp. 79-83 ◽

Cited By ~ 15

Author(s):

W Abplanalp ◽

MD Scheiber ◽

K Moon ◽

B Kessel ◽

JH Liu ◽

...

Keyword(s):

Density Lipoprotein ◽

Antioxidant Effect ◽

High Density ◽

In Vivo Studies ◽

Ldl Oxidation ◽

High Density Lipoproteins ◽

Oh Groups

Estrogens possess strong antioxidant effects in vitro, but in vivo studies in humans have yielded conflicting results. Little is known regarding factors that mediate the antioxidant effect of estrogens in vivo. In this study the potential role of high density lipoprotein (HDL) was examined. The antioxidant effect of estradiol-17beta (E2) added to low density lipoprotein (LDL) was lost after dialysis. In contrast, the antioxidant effect of E2 added to HDL was conserved after dialysis, suggesting that E2 was bound to HDL. Binding of E2 to LDL increased after esterification (especially to long chain fatty acids). In the presence of HDL, an increased amount of E2 was transferred to LDL. E2-17 ester was as potent as E2 in preventing LDL oxidation in vitro, but 3,17-diesters were not as effective (E2=E2-17 ester>E2-3 ester>E2-3,17 diester). This was also supported by experiments which showed that estrogens with masked 3-OH groups were not effective as antioxidants. These studies provide evidence that HDL could facilitate the antioxidant effect of E2 through initial association, esterification and eventual transfer of E2 esters to LDL. Therefore it is critical that HDL peroxidation parameters be evaluated in subjects receiving estrogen replacement therapy.

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