Akahane Shogo, Matsuura Hiroto, Kaido Takahiro, Usami Yoko, Ishimine Nau, Uehara Takeshi, Yamauchi Kazuyoshi
Department of Clinical Laboratory Investigation, 34808 Graduate School of Medicine, Shinshu University , Matsumoto 390-8621, Japan.
Department of Laboratory Medicine, 34808 Shinshu University Hospital , Matsumoto 390-8621, Japan.
Biol Chem. 2024 Mar 18;405(6):383-393. doi: 10.1515/hsz-2024-0018. Print 2024 Jun 25.
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.
低密度脂蛋白受体相关蛋白（LRP）1介导的载脂蛋白（apo）E含脂蛋白（apoE-LP）代谢与脂多糖（LPS）诱导的炎症反应之间的联系有助于脓毒症的发病机制；然而，其潜在机制尚不清楚。因此，在本研究中，使用补充有LPS和含apoE乳液颗粒（apoE-EP）的人成纤维细胞培养系统，评估了apoE-LP及其成分对白细胞介素（IL）-6和LRP1 mRNA表达的影响。利用荧光标记的LPS与血清脂蛋白组分之间的相互作用，检测了apoE-LP对LPS的亲和力。LPS诱导的炎症显著上调了IL-6和LRP1的mRNA表达。用apoE-EP或其成分（apoE或EP）预孵育LPS可显著抑制这种上调。在存在LRP1抑制剂乳铁蛋白的情况下，apoE-EP对IL-6上调的抑制作用减弱。制备的apoE-EP和富含血清甘油三酯的脂蛋白对LPS表现出显著的亲和力。然而，基于用apoE-EP预孵育LPS抑制IL-6上调的程度，这些亲和力似乎低于预期。总体而言，这些结果表明，LPS诱导的炎症可能受以下因素调节：1）apoE-LP的LPS中和作用；2）apoE的抗炎作用；3）LRP1介导的代谢途径。
