Objective

Gut-derived inflammatory factors can impair glucose homeostasis, but the underlying mechanisms are not fully understood. In this study, we investigated how hepatic gene expression is regulated by gut colonization status through myeloid differentiation primary response 88 (MYD88) and how one of the regulated genes, lipopolysaccharide-binding protein (Lbp), affects insulin signaling and systemic glucose homeostasis.

Methods

Liver transcriptomics analysis was conducted on four groups of mice fed a chow diet: conventionally raised (CONV-R) wild-type, germ-free (GF) wild-type, CONV-R Myd88 KO, and GF Myd88 KO. Primary hepatocytes were exposed to combinations of lipopolysaccharide (LPS), LBP, and the LBP-blocking peptide LBPK95A, and the effect on insulin signaling was determined. To assess how LBP affects glucose metabolism in vivo, two mouse models were applied: treatment with LBPK95A and hepatic knockdown of Lbp using CRISPR-CAS9.

Results

We showed that the colonization status regulates gene expression in the liver and that a subset of these genes, including Lbp, is regulated through MYD88. Furthermore, we demonstrated that LBP impairs insulin signaling in hepatocytes in the presence of low levels of LPS and that the effect of LBP is abolished by LBPK95A. We showed that both systemic pharmacological blocking of LBP by LBPK95A and CRISPR-CAS9-mediated downregulation of hepatic Lbp improve glucose homeostasis.

Conclusions

Our results demonstrate that the gut microbiota regulates hepatic expression of Lbp through MYD88-dependent signaling. LBP potentiates LPS inhibition of insulin signaling in vitro and impairs systemic glucose homeostasis in vivo.

中文翻译：

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肠道菌群通过Myd88诱导脂多糖结合蛋白（Lbp）的肝表达，并损害了肥胖小鼠的糖耐量。

目的

肠源性炎性因子可损害葡萄糖稳态，但其潜在机制尚不完全清楚。在这项研究中，我们调查了肝脏基因表达如何通过髓样分化初级反应88（MYD88）受到肠道定植状态的调控，以及调控的基因之一脂多糖结合蛋白（Lbp）如何影响胰岛素信号传导和系统性葡萄糖稳态。

方法

肝转录组学分析是在四组喂了粗饲料的小鼠上进行的：常规饲养的（CONV-R）野生型，无菌（GF）野生型，CONV-R Myd88 KO和GF Myd88 KO。将原代肝细胞暴露于脂多糖（LPS），LBP和LBP阻断肽LBPK95A的组合，并测定了对胰岛素信号传导的影响。为了评估LBP如何影响体内葡萄糖代谢，应用了两种小鼠模型：用LBPK95A治疗和使用CRISPR-CAS9肝敲除Lbp。

结果

我们表明定居状态调节肝脏中的基因表达，并且这些基因的一个子集（包括Lbp）通过MYD88进行调节。此外，我们证明了LBP在低水平LPS的存在下会损害肝细胞中的胰岛素信号传导，并且LBPK95A消除了LBP的作用。我们显示，LBPK95A对LBP的全身性药理阻断和CRISPR-CAS9介导的肝Lbp下调均可以改善葡萄糖稳态。

结论

我们的结果表明，肠道菌群通过MYD88依赖性信号传导调节Lbp的肝表达。LBP在体外增强LPS对胰岛素信号的抑制作用，并损害体内全身葡萄糖稳态。