Abstract
The linkage between low-density lipoprotein receptor-related protein (LRP)1-mediated metabolism of apolipoprotein (apo) E-containing lipoproteins (apoE-LP) and the lipopolysaccharide (LPS)-induced inflammatory response contributes to the pathogenesis of sepsis; however, the underlying mechanisms are unclear. Therefore, in this study, the effects of apoE-LP and their constituents on the mRNA expression of interleukin (IL)-6 and LRP1 were evaluated using a culture system of human fibroblasts supplemented with LPS and apoE-containing emulsion particles (apoE-EP). The affinity of apoE-LP for LPS was examined using the interaction between fluorescence-labeled LPS and serum lipoprotein fractions. LPS-induced inflammation significantly upregulated the mRNA expression of IL-6 and LRP1. This upregulation was markedly suppressed by pre-incubation of LPS with apoE-EP or its constituents (apoE or EP). The suppressive effect of apoE-EP on IL-6 upregulation was attenuated in the presence of lactoferrin, an inhibitor of LRP1. The prepared apoE-EP and serum triglyceride-rich lipoproteins showed significant affinity for LPS. However, these affinities appeared to be lower than expected based on the extent to which IL-6 upregulation was suppressed by pre-incubation of LPS with apoE-EP. Overall, these results indicate that LPS-induced inflammation may be regulated by 1) the LPS-neutralizing effect of apoE-LP, 2) anti-inflammatory effect of apoE, and 3) LRP1-mediated metabolic pathways.
Funding source: Japan Society for the Promotion of Science
Award Identifier / Grant number: JSPS KAKENHI Grant Number 21K07310
Acknowledgments
We gratefully acknowledge the advice and encouragement provided by Dr. Takeshi Uehara (Department of Laboratory Medicine, Shinshu University Hospital).
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Research ethics: The present study was approved by the Ethical Review Board of Shinshu University School of Medicine (approval number, 5762).
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Author contributions: Kazuyoshi Yamauchi designed the present project. Shogo Akahane, Hiroto Matsuura, Takahiro Kaido, Yoko Usami, Nau Ishimine and Kazuyoshi Yamauchi carried out experiments and analyzed experimental data. Shogo Akahane wrote this manuscript. Kazuyoshi Yamauchi and Takeshi Uehara reviewed and commented on drafts of the manuscript. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: The authors declare no conflict of interest associated with this manuscript. The research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Research funding: This research was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number 21K07310 to Kazuyoshi Yamauchi).
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Data availability: The raw data can be obtained on request from the corresponding author [Kazuyoshi Yamauchi].
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Supplementary Material
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