Laboratory of Infection and Prevention, Department of Biological Response, Institute for Virus Research, Kyoto University, and Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kawahara-cho, Sakyo-ku Kyoto, Japan.
Crit Care Med. 2010 Dec;38(12):2345-51. doi: 10.1097/CCM.0b013e3181f85b2a.
Endotoxin triggers a reorganization of the energy metabolic pathway, including the promotion of fatty acid utilization to adapt to a high energy demand during endotoxemia. However, the factors responsible for the metabolic adaptation and characteristic pathologies resulting from defective utilization fatty acids during endotoxin response have not been fully clarified. The thioredoxin binding protein-2 (TBP-2) knockout (TBP-2) mouse is an animal model of fatty acid oxidation disorder. The aim of this study was to determine whether and how TBP-2 is involved in metabolic regulation in a lipopolysaccharide (LPS)-induced endotoxemia model in mice.
Prospective animal trial.
Research laboratory.
TBP-2 and wild control mice.
TBP-2 and wild control mice were intraperitoneally injected with LPS. Mortality, serum levels of markers of hepatorenal injuries, cytokines, insulin, glucose and lipid derivatives, and the hepatic signaling pathway regulating gluconeogenesis were investigated.
Following the administration of LPS, TBP-2 mice showed a predisposition for death without any significant elevation of inflammatory cytokines, compared to the wild mice. LPS-challenged TBP-2 mice showed fat deposition in the liver and kidney, organ injuries, glycogen depletion, and elevation of serum lipid derivatives such as free fatty acids, triglyceride and cholesterol. Hyperinsulinemia and hypoglycemia were observed in TBP-2 mice after LPS injection. Death due to the LPS administration was prevented by supplementation of glucose. Phosphorylation of Akt and FoxO1, an inhibitory pathway of gluconeogenesis in the liver of LPS-challenged TBP-2 mice was demonstrated, suggesting the enhancement of insulin signaling.
TBP-2 is involved in metabolic control during LPS-induced endotoxemia. After the LPS challenge, TBP-2 mice showed several characteristic aspects, such as hepatorenal injuries, and dysregulation of the lipid and glucose metabolisms. Furthermore, hypoglycemia promoted by hyperinsulinemia may be a critical risk factor for mortality in circumstances in which fatty acid utilization is impaired during endotoxemia.
内毒素触发能量代谢途径的重新组织，包括促进脂肪酸利用以适应内毒素血症期间的高能量需求。然而，导致代谢适应的因素以及内毒素反应期间脂肪酸利用缺陷导致的特征性病理尚未完全阐明。硫氧还蛋白结合蛋白-2（TBP-2）敲除（TBP-2）小鼠是一种脂肪酸氧化障碍的动物模型。本研究旨在确定 TBP-2 是否以及如何参与脂多糖（LPS）诱导的内毒素血症模型中小鼠的代谢调节。
前瞻性动物试验。
研究实验室。
TBP-2 和野生对照小鼠。
TBP-2 和野生对照小鼠经腹腔注射 LPS。研究了死亡率、肝肾功能损伤标志物、细胞因子、胰岛素、葡萄糖和脂质衍生物水平以及调节糖异生的肝信号通路。
给予 LPS 后，与野生型小鼠相比，TBP-2 小鼠表现出死亡倾向，而炎症细胞因子无明显升高。LPS 挑战的 TBP-2 小鼠表现出肝脏和肾脏脂肪沉积、器官损伤、糖原耗竭以及血清脂质衍生物（如游离脂肪酸、甘油三酯和胆固醇）升高。LPS 注射后 TBP-2 小鼠出现高胰岛素血症和低血糖。补充葡萄糖可预防 LPS 给药引起的死亡。LPS 挑战的 TBP-2 小鼠肝脏中糖异生的抑制途径 Akt 和 FoxO1 的磷酸化表明胰岛素信号增强。
TBP-2 参与 LPS 诱导的内毒素血症期间的代谢控制。在 LPS 挑战后，TBP-2 小鼠表现出多种特征性方面，如肝肾功能损伤以及脂质和葡萄糖代谢失调。此外，内毒素血症期间脂肪酸利用受损时，高胰岛素血症引起的低血糖可能是死亡率的关键危险因素。
