Although hypoglycemia has been documented as a major cause of high mortality in the setting of septic shock, the mechanism of hypoglycemia in infection has not been clearly determined. Hepatic gluconeogenesis serves as an important mechanism to maintain glucose levels under physiological conditions and CREB coactivator CRTC2 plays an important role in regulating gluconeogenic gene expression. Here, we show that triggering of the Toll-like receptor 4 pathway in response to endotoxin lipopolysaccharide (LPS) inhibits gluconeogenic gene expression and hepatic glucose output by blocking CRTC2 activation. Interleukin-1β (IL-1β) is found to disrupt gluconeogenic gene expression via the activation of the E3 ubiquitin ligase TRAF6, a key component of the Toll-like receptor 4 signaling pathway that associates with and ubiquitinates CRTC2. TRAF6 promotes the K63-linked ubiquitination of CRTC2, a modification that blocks binding of calcineurin at an adjacent calcineurin-binding site, thereby disrupting CRTC2 dephosphorylation in response to glucagon signals. Mutation of TRAF6-binding sites or ubiquitination site in CRTC2 rescues hepatic gluconeogenesis in LPS-challenged mice. These results suggest that pro-inflammatory signals intersect with the CRTC2 pathway in liver, thus contributing to hypoglycemia caused by infection.

中文翻译：

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TRAF6对CRTC2介导的肝糖异生的抑制作用导致败血性休克的低血糖症。

尽管低血糖已被证明是败血性休克高死亡率的主要原因，但尚未明确确定感染中低血糖的机制。肝糖异生是在生理条件下维持葡萄糖水平的重要机制，CREB辅助激活物CRTC2在调节糖异生基因表达中起重要作用。在这里，我们显示响应内毒素脂多糖（LPS）触发Toll样受体4途径通过阻断CRTC2激活抑制糖异生基因表达和肝葡萄糖输出。发现白介素-1β（IL-1β）通过激活E3泛素连接酶TRAF6来破坏糖原异生基因表达，E3泛素连接酶TRAF6是Toll样受体4信号传导途径的关键组成部分，与CRTC2缔合并泛素化。TRAF6促进CRTC2的K63连接泛素化，该修饰可阻断钙调神经磷酸酶在相邻钙调神经磷酸酶结合位点的结合，从而响应胰高血糖素信号而破坏CRTC2的去磷酸化。CRTC2中TRAF6结合位点或泛素化位点的突变可挽救LPS攻击小鼠的肝糖异生。这些结果表明促炎信号与肝脏中的CRTC2途径相交，从而导致了由感染引起的低血糖症。