Lipopolysaccharide inhibition of glucose production through the Toll-like receptor-4, myeloid differentiation factor 88, and nuclear factor kappa b pathway.
Lipopolysaccharide inhibition of glucose production through the Toll-like receptor-4, myeloid differentiation factor 88, and nuclear factor kappa b pathway.
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DOI：
10.1002/hep.22999
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发表时间：
2009-08
期刊：
影响因子：
13.5
通讯作者：
Combs, Terry P.
中科院分区：
文献类型：
--
作者：
Raetzsch, Carl F.;Brooks, Natasha L.;Alderman, J. McKee;Moore, Kelli S.;Hosick, Peter A.;Klebanov, Simon;Akira, Shizuo;Bear, James E.;Baldwin, Albert S.;Mackman, Nigel;Combs, Terry P.
急性暴露于脂多糖(LPS)可导致低血糖和胰岛素抵抗；然而，其潜在机制尚不清楚。我们试图通过TLR4、MyD88和核因子κB来确定胰岛素抵抗是否与低血糖有关，这是一条细胞信号通路，介导了内毒素诱导促炎细胞因子α的产生。TLR4−/−和MYD88−/−小鼠的内毒素诱导的低血糖作用被阻断，而肿瘤坏死因子α−/−小鼠的内毒素诱导的低血糖作用没有被阻断。低血糖时葡萄糖产量和葡萄糖利用率均下降。低血糖与肝脏中核因子κB的活化有关。从TLR4−/−和MyD88−/−小鼠分离的肝细胞和表达干扰NFκB激活的IκB突变体的肝癌细胞中，内毒素对葡萄糖产生的抑制被阻断。因此，内毒素诱导的低血糖是通过TLR4、MyD88、NFκB途径抑制肝脏葡萄糖产生而实现的，而不依赖于内毒素诱导的α。药物对肝癌细胞中胰岛素信号中间产物PI3K的抑制不能阻断脂多糖对葡萄糖产生的抑制作用。注射胰岛素对TLR4−/−和TLR4+/+小鼠的循环血糖有类似的降低作用。这两个结果表明，内毒素和胰岛素通过不同的途径抑制葡萄糖的产生。在TLR4+/+小鼠中，从脂多糖诱导的低血糖中恢复与葡萄糖耐量和高胰岛素血症有关，而在TLR4−/−小鼠中则不相关。胰岛素抵抗与TLR4、MyD88和NFκB途径抑制葡萄糖生成有关。
Acute exposure to lipopolysaccharide (LPS) can cause hypoglycemia and insulin resistance; the underlying mechanisms however, are unclear. We set out to determine whether insulin resistance is linked to hypoglycemia through TLR4, MyD88 and NFκB, a cell signaling pathway that mediates LPS induction of the proinflammatory cytokine TNFα. LPS induction of hypoglycemia was blocked in TLR4−/− and MyD88−/− mice but not in TNFα−/− mice. Both glucose production and glucose utilization were decreased during hypoglycemia. Hypoglycemia was associated with the activation of NFκB in the liver. LPS inhibition of glucose production was blocked in hepatocytes isolated from TLR4−/− and MyD88−/− mice and hepatoma cells expressing an IκB mutant that interferes with NFκB activation. Thus, LPS-induced hypoglycemia was mediated by the inhibition of glucose production from the liver through the TLR4, MyD88, NFκB pathway, independent of LPS induced TNFα. LPS inhibition of glucose production was not blocked by pharmacologic inhibition of the insulin signaling intermediate PI3K in hepatoma cells. Insulin injection caused a similar reduction of circulating glucose in TLR4−/− and TLR4+/+ mice. These two results suggest that LPS and insulin inhibit glucose production by separate pathways. Recovery from LPS induced hypoglycemia was linked to glucose intolerance and hyperinsulinemia in TLR4+/+ mice, but not in TLR4−/− mice. Insulin resistance is linked to the inhibition of glucose production by the TLR4, MyD88 and NFκB pathway.
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影响因子：
5.8
作者：
Agwunobi, AO;Reid, C;Carlson, GL
通讯作者：
Carlson, GL
影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
DOI：
10.1006/bbrc.1994.2510
发表时间：
1994-10-28
影响因子：
3.1
作者：
HORTON, RA;KNOWLES, RG;TITHERADGE, MA
通讯作者：
TITHERADGE, MA
影响因子：
15.9
作者：
Combs, TP;Berg, AH;Rossetti, L
通讯作者：
Rossetti, L
影响因子：
4.8
作者：
Cao, WH;Collins, QF;Collins, S
通讯作者：
Collins, S