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Serum amyloid A impairs the antiinflammatory properties of HDL
Chang Yeop Han, … , Keith B. Elkon, Alan Chait
Chang Yeop Han, … , Keith B. Elkon, Alan Chait
Published December 7, 2015
Citation Information: J Clin Invest. 2016;126(1):266-281. https://doi.org/10.1172/JCI83475.
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Research Article Inflammation Metabolism

Serum amyloid A impairs the antiinflammatory properties of HDL

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Abstract

HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface–associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane.

Authors

Chang Yeop Han, Chongren Tang, Myriam E. Guevara, Hao Wei, Tomasz Wietecha, Baohai Shao, Savitha Subramanian, Mohamed Omer, Shari Wang, Kevin D. O’Brien, Santica M. Marcovina, Thomas N. Wight, Tomas Vaisar, Maria C. de Beer, Frederick C. de Beer, William R. Osborne, Keith B. Elkon, Alan Chait

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Figure 4

HDL from AgNO3-injected mice colocalizes with the adipocyte cell surface.

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HDL from AgNO3-injected mice colocalizes with the adipocyte cell surface...
(A) HDL from PBS- and AgNO3-injected C57BL/6 mice was labeled with DiI (red). After exposure to these HDL preparations (50 μg protein/ml) for 6 hours, 3T3-L1 adipocytes were fixed in 2% formalin for 5 minutes. To distinguish the outside of cells from intracellular sites, the cell surface–associated ECM was stained with Alexa Fluor 488–conjugated WGA (green). Cell nuclei were counterstained with DAPI (blue). Cell morphology was shown by phase-contrast photography (left panels). Merged fluorescence (overlay) is shown in yellow. Original magnification, ×400. When the cell surface–associated ECM of 3T3-L1 adipocytes was digested with chondroitin ABC lyase and heparitinase for 1 hour prior to exposure to HDL, colocalization of HDL from AgNO3-injected mice with the cell surface (row 2, column 5) was lost and resulted in a similar distribution of dye to that seen with control HDL (row 3, column 5). (B and C) Enzyme digestion of the proteoglycans in the ECM also restored the impaired cholesterol efflux observed with HDL from AgNO3-injected mice (B) and Saa3 gene expression (C). Representative fluorescence images of 3 independent experiments are shown. Data represent mean ± SD. Data are representative of at least 3 independent experiments. *P < 0.001 vs. C57BL/6 HDL (AgNO3), **P < 0.001 vs. AgNO3-HDL. ANOVA and Bonferroni post-hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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