肠道菌群如何作用于肝脏影响血糖调控?
  • 分析敲除或未敲除骨髓分化因子Myd88基因的野生型和无菌小鼠的肝脏转录组,发现肠道菌群可通过Myd88诱导肝脏表达脂多糖结合蛋白基因(Lbp);
  • 细胞培养发现,1ng/mL脂多糖(LPS)即可间接诱导肝细胞表达Lbp基因,并可加强脂多糖结合蛋白(LBP)损害肝细胞胰岛素信号的能力;
  • 用LBP阻断蛋白干预小鼠,发现其葡萄糖耐受性相比对照组得到改善;
  • 敲除小鼠肝脏Lbp基因降低其肝脏LBP水平,能降低小鼠空腹血糖水平,但不影响肥胖或脂肪肝等。
主编推荐语
潇洒小姐陈
现已知西化饮食、肥胖和葡萄糖稳态失衡与血浆中增多的脂多糖(LPS)浓度相关,而LPS在健康人体或瘦小鼠体内也存在,因此作者想探究LPS是否在不影响肥胖的情况下破坏血糖代谢。骨髓分化因子Myd88是LPS的转化分子,帮助LPS激活下游目标。作者巧妙的利用了敲除或未敲除Myd88基因的野生型和无菌小鼠,找出了由菌群通过Myd88调控的肝脏基因。作者选取了与血糖失衡和2型糖尿病相关的脂多糖结合蛋白基因(Lbp),随后进行了一系列的细胞培养实验和动物实验,证明肝脏脂多糖结合蛋白(LBP)会损坏胰岛素信号和破坏葡萄糖耐受,但并不影响肥胖和脂肪等其它问题。
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Hepatic expression of Lipopolysaccharide Binding Protein (Lbp) is induced by the gut microbiota through Myd88 and impairs glucose tolerance in mice independent of obesity

肠道菌群通过Myd88诱导肝脏脂多糖结合蛋白(Lbp)的表达并独立于肥胖破坏葡萄糖耐受性

10.1016/j.molmet.2020.100997

2020-04-16, Article

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Objective: Gut derived inflammatory factors can impair glucose homeostasis but the underlying mechanisms are not fully understood. Here we investigate 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 performed 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 showed that LBP impairs insulin signalling in hepatocytes in the presence of low levels of LPS and that that the effect of LBP is abolished by LBPK95A. Finally, 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 as well as impairs systemic glucose homeostasis in vivo.

First Authors:
Antonio Molinaro,Ara Koh

Correspondence Authors:
Robert Caesar

All Authors:
Antonio Molinaro,Ara Koh,Hao Wu,Marc Schoeler,Ilaria Faggi,Alba Carreras,Anna Hallen,Fredrik Bäckhed,Robert Caesar

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