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J Clin Endocrinol Metab. 2009 Feb 17. [Epub ahead of print]

Role of adipocyte serum amyloid A in paracrine cross-talk between adipocytes and macrophages in cholesterol efflux.

Poitou C, Divoux A, Faty A, Tordjman J, Hugol D, Aissat A, Keophiphath M, Henegar C, Commans S, Clément K.

Inserm, U872 team7, Nutriomique, Cordelier Research Center, Paris, 75006, France; University Pierre et Marie Curie-Paris-6, UMRS, Paris, 75006, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Endocrinology and Nutrition Department, Pitié Salpêtrière hospital, Paris, 75013, France, France; GlaxoSmithKline Laboratory, Research Centre metabolic Pathways CEDD GlaxoSmithKline, Les Ulis, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Cytopathology department, Hotel Dieu Hospital, Paris, F-75004; Assistance Publique-Hôpitaux de Paris (AP-HP), Surgery department, Hotel Dieu Hospital Paris, F-75004.

Context: 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. Objective: We aimed to investigate the role and regulation of A-SAA in human adipose tissue (AT). Design: An approach combining microarrays and the FunNet bioinformatic tool was applied to human AT fractions (i.e. Adipocytes vs. Stroma Vascular Fraction, SVF) 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. Results: Microarray analysis highlighted the relationship between A-SAA and SVF inflammatory genes and between A-SAA and adipocyte-expressed ATP-binding cassette (ABC) transporters. We confirmed that SAA protein is expressed in subcutaneous AT of obese subjects (N=37, BMI = 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 ABCA1 (ABC sub family A1) protein expression (R=0.43, p=9.10(-3)). Interleukin-1beta, Tumor Necrosis Factor alpha and human AT macrophages conditioned medium significantly induced A-SAA secretion (from 2.6 to 7.6 fold) in hMADS cells. Recombinant SAA induced cholesterol ABCA1-dependent efflux from hMADS adipocytes by 4.3-fold in a dose-dependent manner. Conclusion: 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.