Palmitate and minimally-modified low-density lipoprotein cooperatively promote inflammatory responses in macrophages.

Soo-Jin Ann,Inhwa Hwang,Yury I Miller,Sungha Park,Sang-Hak Lee,Je-Wook Yu,Hye-Min Noh,Seok-Min Kang,Sangwoo Kim,Ichiro Manabe,Eun Jeong Cheon,Ka-Kyung Kim

doi:10.1371/journal.pone.0193649

Abstract

Increased consumption of Western-type diets and environmental insults lead to wide-spread increases in the plasma levels of saturated fatty acids and lipoprotein oxidation. The aim of this study is to examine whether palmitate and minimally modified low-density lipoprotein (mmLDL) exert an additive effect on macrophage activation. We found that CXCL2 and TNF-α secretion as well as ERK and p38 phosphorylation were additively increased by co-treatment of J774 macrophages with palmitate and mmLDL in the presence of lipopolysaccharide (LPS). Furthermore, the analysis of differentially expressed genes using the KEGG database revealed that several pathways, including cytokine-cytokine receptor interaction, and genes were significantly altered. These results were validated with real-time PCR, showing upregulation of Il-6, Csf3, Il-1β, and Clec4d. The present study demonstrated that palmitate and mmLDL additively potentiate the LPS-induced activation of macrophages. These results suggest the existence of synergistic mechanisms by which saturated fatty acids and oxidized lipoproteins activate immune cells.

Highlights

Saturated fatty acids (SFA) and oxidized lipoproteins, which are commonly found in environments with excess nutrients or highly oxidative conditions, are known to mediate atherosclerosis
Cytokine secretion in cells treated with palmitate or minimally modified low-density lipoprotein (mmLDL) alone tended to increase, the difference compared to the control was not statistically significant (Fig 1A)
This study demonstrated that treatment with palmitate and mmLDL additively promotes macrophage activation by low-dose LPS

Summary

Introduction

Saturated fatty acids (SFA) and oxidized lipoproteins, which are commonly found in environments with excess nutrients or highly oxidative conditions, are known to mediate atherosclerosis. While the central role of adipocytes in systemic energy homeostasis has been established [1], increased free fatty acids released from fat tissue emerged as a significant factor contributing to metabolic disorders, lipotoxicity, and vascular diseases [2,3]. Technology Development Program of the NRF funded by the Korean government, MSIP (2015M3A9B6029138) (SH Lee), the National Research Council of Science & Technology (NST) grant by the Korean government (MSIP) (No CAP12-2-KBSI) (SH Lee), a faculty research grant of Yonsei University College of Medicine (6-20160081) (S Kim), and a grant HL135737 from the US National Institute of Health (Y.I.Miller). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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