Serum Amyloid A Stimulates Vascular and Renal Dysfunction in Apolipoprotein E-Deficient Mice Fed a Normal Chow Diet

Acute serum amyloid A (SAA) is an apolipoprotein that mediates pro-inflammatory and pro-atherogenic pathways. SAA-mediated signalling is diverse and includes canonical and acute immunoregulatory pathways in a range of cell types and organs. This study aimed to further elucidate the roles for SAA in the pathogenesis of vascular and renal dysfunction. Two groups of male ApoE-deficient mice were administered SAA (100 µL, 120 µg/mL) or vehicle control (100 µL PBS) and monitored for 4 or 16 weeks after SAA treatment; tissue was harvested for biochemical and histological analyses at each time point. Under these conditions, SAA administration induced crosstalk between NF-κB and Nrf2 transcriptional factors, leading to downstream induction of pro-inflammatory mediators and antioxidant response elements 4 weeks after SAA administration, respectively. SAA treatment stimulated an upregulation of renal IFN-γ with a concomitant increase in renal levels of p38 MAPK and matrix metalloproteinase (MMP) activities, which is linked to tissue fibrosis. In the kidney of SAA-treated mice, the immunolocalisation of inducible nitric oxide synthase (iNOS) was markedly increased, and this was localised to the parietal epithelial cells lining Bowman’s space within glomeruli, which led to progressive renal fibrosis. Assessment of aortic root lesion at the study endpoint revealed accelerated atherosclerosis formation; animals treated with SAA also showed evidence of a thinned fibrous cap as judged by diffuse collagen staining. Together, this suggests that SAA elicits early renal dysfunction through promoting the IFN-γ-iNOS-p38 MAPK axis that manifests as the fibrosis of renal tissue and enhanced cardiovascular disease.

Download Full-text

Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽

10.1210/en.2008-0971 ◽

2009 ◽

Vol 150 (5) ◽

pp. 2109-2117 ◽

Cited By ~ 244

Author(s):

Elodie Riant ◽

Aurélie Waget ◽

Haude Cogo ◽

Jean-François Arnal ◽

Rémy Burcelin ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Intolerance ◽

High Fat Diet ◽

Chow Diet ◽

High Fat ◽

Normal Chow ◽

Visceral Adipose ◽

Deficient Mice ◽

Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

Download Full-text

Serum amyloid A is not incorporated into HDL during HDL biogenesis

The Journal of Lipid Research ◽

10.1194/jlr.ra119000329 ◽

2020 ◽

Vol 61 (3) ◽

pp. 328-337 ◽

Cited By ~ 2

Author(s):

Ailing Ji ◽

Xuebing Wang ◽

Victoria P. Noffsinger ◽

Drew Jennings ◽

Maria C. de Beer ◽

...

Keyword(s):

Adenoviral Vector ◽

Serum Amyloid A ◽

Scavenger Receptor ◽

Serum Amyloid ◽

Type I ◽

Primary Hepatocytes ◽

Amyloid A ◽

Scavenger Receptor Class ◽

Class B ◽

Deficient Mice

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.

Download Full-text

Confusion of apolipoprotein E phenotyping by serum amyloid A.

Clinical Chemistry ◽

10.1093/clinchem/35.4.671a ◽

1989 ◽

Vol 35 (4) ◽

pp. 671-672 ◽

Cited By ~ 8

Author(s):

A Steinmetz ◽

R Saïle ◽

M Sefraoui ◽

H J Parra ◽

J C Fruchart

Keyword(s):

Apolipoprotein E ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Amyloid A

Download Full-text

Adenoviral vector-mediated overexpression of serum amyloid A in apoA-I-deficient mice

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)37176-5 ◽

1997 ◽

Vol 38 (8) ◽

pp. 1583-1590

Author(s):

N R Webb ◽

M C de Beer ◽

D R van der Westhuyzen ◽

M S Kindy ◽

C L Banka ◽

...

Keyword(s):

Adenoviral Vector ◽

Serum Amyloid A ◽

Serum Amyloid ◽

Amyloid A ◽

Deficient Mice

Download Full-text

High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21041316 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1316 ◽

Cited By ~ 2

Author(s):

Xiaoping Cai ◽

Gulfam Ahmad ◽

Farjaneh Hossain ◽

Yuyang Liu ◽

XiaoSuo Wang ◽

...

Keyword(s):

Renal Function ◽

High Density Lipoprotein ◽

Apolipoprotein E ◽

Serum Amyloid A ◽

Density Lipoprotein ◽

High Density ◽

Serum Amyloid ◽

Vascular Lesions ◽

Aortic Lesion ◽

Amyloid A

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.

Download Full-text