Glutamine Modulates Hepatic Akt/Mtorc2/Foxo1 Pathway in Mice with Polymicrobial Sepsis.

Sepsis is a complication commonly occurred in critically ill patients. Multi-organ failure is the main cause of death during sepsis. Among all organs infected by sepsis, liver dysfunction was rarely studied, because it usually happens at very late stage that may not be observed at the early phase of sepsis. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that control proliferation, nutrition status and energy metabolism of the cells. There are 2 complex subtypes of mTOR: mTORC1 and mTORC2. mTORC2 plays a critical role in inflammatory immune response in liver. The regulatory mechanisms are not fully clarified. mTORC2 was found to activate PI3K/Akt/FoxO1 signal pathway, promotes the polarization of macrophage towards M2 type in kupffer cells (KC) and alleviates the inflammation of liver tissue. Glutamine (GLN) is a metabolic fuel for immune cells. Plasma GLN concentrations decrease during sepsis and GLN supplementation improves the prognosis of patients with sepsis. Previous study revealed that GLN activates mTOR pathways under normal conditions. However, no study investigated the impact of GLN on PI3K/Akt/FoxO1 pathway and M1/M2 ratio in liver tissue. Therefore, we propose to carry out this series study in 3 consecutive years to investigate the effects of GLN on hepatic mTORC2 signaling in macrophage polarization and immune regulation during sepsis. In the first year, we plan to conduct in vitro study to investigate whether GLN modulates TLR4/PI3K/Akt /mTORC2/FoxO1 pathway and M1/M2 ratio in lipopolysaccharide (LPS)-stimulated KC. In the second year, conditioned medium secreted by LPS-stimulated KC was co-cultured with primary mice hepatocyte to investigate the effects of GLN on changes of IRS/Akt/ mTORC2 /FoxO1 pathway and the immunomodulation of hepatocytes. In order to confirm the role of GLN in in vivo conditions, an animal study will be carried out in the third year. GLN was parenterally infused to evaluate the efficacy of GLN on IRS/PI3K/Akt/mTORC2 /FoxO1 pathway and immune regulation is septic mice. This study may provide useful information of GLN supplementation in patients with sepsis.