Serum amyloid A-containing HDL binds adipocyte-derived versican and macrophage-derived biglycan, reducing its antiinflammatory properties.

Chang Yeop Han,Inkyung Kang,Mohamed Omer,Tomasz Wietecha,Thomas N Wight,Alan Chait,Shari Wang

doi:10.1172/jci.insight.142635

Abstract

The ability of HDL to inhibit inflammation in adipocytes and adipose tissue is reduced when HDL contains serum amyloid A (SAA) that is trapped by proteoglycans at the adipocyte surface. Because we recently found that the major extracellular matrix proteoglycan produced by hypertrophic adipocytes is versican, whereas activated adipose tissue macrophages produce mainly biglycan, we further investigated the role of proteoglycans in determining the antiinflammatory properties of HDL. The distributions of versican, biglycan, apolipoprotein A1 (the major apolipoprotein of HDL), and SAA were similar in adipose tissue from obese mice and obese human subjects. Colocalization of SAA-enriched HDL with versican and biglycan at the cell surface of adipocyte and peritoneal macrophages, respectively, was blocked by silencing these proteoglycans, which also restored the antiinflammatory property of SAA-enriched HDL despite the presence of SAA. Similar to adipocytes, normal HDL exerted its antiinflammatory function in macrophages by reducing lipid rafts, reactive oxygen species generation, and translocation of Toll-like receptor 4 and NADPH oxidase 2 into lipid rafts, effects that were not observed with SAA-enriched HDL. These findings imply that SAA present in HDL can be trapped by adipocyte-derived versican and macrophage-derived biglycan, thereby blunting HDL’s antiinflammatory properties.

Highlights

Chronic caloric excess from glucose or fatty acids leads to obesity, which is characterized by accumulation of macrophages in adipose tissue in response to chemotactic factors generated by adipocytes [1,2,3]
We subsequently have shown that versican derived from adipocytes and biglycan derived from adipose tissue macrophages were increased in obesity [17]
To further understand the role of these proteoglycans in the retention of serum amyloid A (SAA)-enriched HDL, immunostaining for apolipoprotein A1 (APOA1) and SAA was performed on adjacent sections of adipose tissues from our previous study [17], in which C57BL/6 mice were made obese by feeding an HFHS diet for 16 weeks, and adjacent sections of human omental adipose tissue from gastric bypass patients

Summary

Introduction

Chronic caloric excess from glucose or fatty acids leads to obesity, which is characterized by accumulation of macrophages in adipose tissue in response to chemotactic factors generated by adipocytes [1,2,3]. Both adipocytes and macrophages secrete a number of proinflammatory molecules, which may lead to chronic low-grade inflammation and insulin resistance in obesity [4,5,6]. One class of ECM molecules that has immunoregulatory properties and that has received little attention in adipose tissue is proteoglycans

Methods

Results

Conclusion