Role of Serum Amyloid A in Adipocyte-Macrophage Cross Talk and Adipocyte Cholesterol Efflux

Institut National de la Santé et de la Recherche Médicale, U872 team7, Nutriomique, Cordelier Research Center, Paris 75006, France.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 03/2009; 94(5):1810-7. DOI: 10.1210/jc.2008-2040
Source: PubMed


Acute phase serum amyloid A (A-SAA) is secreted by hepatocytes in response to injury and is regulated by proinflammatory cytokines. In obese humans, adipocytes are also a major contributor to circulating A-SAA levels.
We aimed to investigate the role and regulation of A-SAA in human adipose tissue (AT).
An approach combining microarrays and the FunNet bioinformatics tool was applied to human AT fractions (i.e. adipocytes vs. stroma vascular fraction) to hypothesize genes and functions related to A-SAA. Experiments with human AT from 37 obese subjects and human multipotent adipose-derived stem (hMADS) cells were used to confirm the microarray driven hypotheses.
Microarray analysis highlighted the relationship between A-SAA and stroma vascular fraction inflammatory genes, and between A-SAA and adipocyte-expressed ATP-binding cassette (ABC) transporters. We confirmed that serum amyloid A (SAA) protein is expressed in sc AT of obese subjects (n = 37, body mass index = 49.3 +/- 1.5 kg/m(2)) and showed that SAA protein expression correlated with adipocyte size (R = 0.44; P = 6.10(-3)), macrophage infiltration (R = 0.61; P = 10(-4)), and ABC subfamily A1 protein expression (R = 0.43; P = 9.10(-3)). IL-1beta, TNF-alpha, and human AT macrophage-conditioned medium significantly induced A-SAA secretion (from 2.6 to 7.6 fold) in hMADS cells. Recombinant SAA induced cholesterol ABC subfamily A1-dependent efflux from hMADS adipocytes by 4.3-fold in a dose-dependent manner.
This work provides original insight suggesting that A-SAA is a player in the dialogue between hypertrophied adipocytes and macrophages through its regulation of adipocyte cholesterol efflux.

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    • "SAA is primarily synthesized by hepatocytes [1], and its extra-hepatic sources include leukocytes [2], adipocytes [3], synoviocytes [4], tumor cells [5] and first trimester trophoblast cells [6]. SAA has been shown to play biological roles in lipid metabolism [7], immunomodulation [8]–[10] and cell proliferation [11], [12] and invasion [13]. "
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    ABSTRACT: The serum amyloid A (SAA) protein is known to function in the acute phase response and immunoregulation. Recently, SAA has been shown to be involved in cell proliferation, differentiation and migratory behavior in different cell types. Here, we evaluated whether exogenous SAA could influence trophoblast invasion and differentiation using both the trophoblast-like BeWo cell line and fully differentiated human extravillous trophoblast cells (EVT) isolated from term placentae. SAA stimulated BeWo cell invasion, as measured in Matrigel invasion assays, and induced metalloprotease mRNA expression and activity. Given that BeWo cells express Toll-like receptor 4 (TLR4), a known receptor for SAA, we examined the role of TLR4 in SAA-induced invasion using a TLR4 neutralizing antibody. We also tested whether SAA could affect markers of trophoblast syncytialization in BeWo cells. We observed that SAA decreased βhCG secretion and did not influence trophoblast syncytialization. Using EVT cells isolated from human term basal plates, we confirmed that SAA at 1 and 10 µg/mL doubled EVT invasion in a TLR4-dependent manner, but at 20 µg/mL inhibited EVT cells invasiveness. In addition, we observed that SAA was expressed in both BeWo cells and human term placentae, specifically in the syncytiotrophoblast, decidual cells and EVT. In conclusion, SAA was identified as a molecule that functions in the placental microenvironment to regulate metalloprotease activity and trophoblast invasion, which are key processes in placentation and placental homeostasis.
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    • "They exhibit stem cell characteristics, i.e. the capacity to self-renew and differentiate into several cell types at the clonal level, even after longterm expansion. Expanded hMADS cells are able to differentiate under serum-free adipogenic conditions into cells displaying a combination of properties similar, if not identical, to those of native human adipocytes [3] [4]. Altogether, hMADS cells appear to be a powerful cellular model to investigate cell surface marker expression during self-renewal and differentiation. "
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    ABSTRACT: Human adipose-derived stem cell populations express cell surface markers such as CD105, CD73, CD146 and CD140a/PDFGRα. However, it was unclear whether these markers could discriminate subpopulations of undifferentiated cells and whether the expression of these markers is modulated during differentiation. To address this issue, we analyzed the immunophenotype of cultured human multipotent adipose derived stem (hMADS) cell populations at different adipocyte differentiation steps. We found that 100% of undifferentiated cells expressed CD73 and CD105. In contrast, CD146 and CD140a/PDFGRα marked two different subpopulations of cells. CD140a/PDGFRα subpopulation was regulated by FGF2, a critical factor of human adipose-derived stem cell self-renewal. During differentiation, CD73 was maintained and marked lipid-laden cells, whereas CD105 expression was inhibited in fully differentiated cells. The percentage of CD146- and CD140a/PDFGRα-positive cells declined as soon as cells had undergone differentiation. Altogether, these data support the notion that expanded adipose-derived stem cells are heterogeneous mixtures of cells and cell surface markers studied can discriminate subpopulations.
    Preview · Article · Dec 2012 · Biochemical and Biophysical Research Communications
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    • "We previously reported that SAA is a player in the dialogue between hypertrophied adipocytes and macrophages through its regulation of adipocyte cholesterol efflux [42]. Taken together, our new data along with the published observation provide further evidence for a central role of SAA in adipocyte-macrophage cross-talks in obesity: 1) SAA increases IL-6 and IL-8 production by adipocytes as well as the chemokine MCP-1, which recruits circulating monocytes into the adipose tissue; 2) SAA increases IL-6, IL-8 and TNFα production by immune cells; 3) SAA displays direct chemoattractant activity in the presence or absence of hyaluronan complexes [15], [33], [41]–[44]. "
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