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

Abstract

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 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.

Results: 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/m²) 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-1β, TNF-α, 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.

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.