High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway.

Guohua Song,Huaxia Liu,Haiming Song,Shucun Qin,Peng Jiao,You Wu,Yang Yu,Mingfeng Yang,Ni Wang,Xiangjian Zhang,Xia Wu,Pu Zhang

doi:10.1038/srep30889

Abstract

Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation.

Highlights

Since the discovery of the adipocyte as a ‘metabolically active organ’ which secretes hormones, cytokines and chemokines, there is growing interest in understanding its functions in obesity and weight loss[1]
We demonstrate that high-density lipoprotein (HDL) may suppress oxidized low-density lipoprotein (ox-LDL)-induced free cholesterol (FC) accumulation in adipocytes through upregulation of scavenger receptor class B type I (SR-BI), subsequently preventing ox-LDL-induced endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP) pathway-mediated adipocyte inflammation
We confirms the protective effects of HDL on adipocyte inflammation, which provides the important link between obesity and its complications

Summary

Introduction

Since the discovery of the adipocyte as a ‘metabolically active organ’ which secretes hormones, cytokines and chemokines, there is growing interest in understanding its functions in obesity and weight loss[1]. Chronic low-grade inflammation is identified as a hallmark in obesity with dysregulation of adipose tissue-derived adipokines production. These are detected in both serum and adipose tissue and are active factors that modulate the effects of obesity and related comorbidities[5,6]. It could be presumed that inhibition of ER stress may be an effective approach to modify adipokines secretion, inhibit inflammation and reduce the risk of obesity and its complications It is well-known that high-density lipoprotein (HDL) has significant anti-inflammatory and anti-atherogenic properties. We investigated the effect of HDL on adipokines secretion and lipid accumulation, with emphasis on its role in downregulating the ER stress-CHOP pathway-mediated inflammation in vitro and in vivo

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Conclusion