SUN-667 Hyperinsulinemia Suppresses Hepatic Autophagy at Late Sepsis in an mTOR-Dependent Transcriptional Regulation

Autophagy transiently occurs in the liver at early stage, while autophagy suppression associated with liver failure occurs at late stage in a CLP (cecal ligation and puncture) model of sepsis. However, the factors that cause autophagy suppression at late sepsis remain unknown. Hyperinsulinemia is observed in early sepsis, and insulin inhibits autophagy via mTOR, which regulates TFEB/ZKSCAN3 nuclear translocation and the transcription of autophagy-related genes (LC3, p62, WIPI2, ATG9 etc.). Thus, we used CLP mouse model of sepsis to test the hypothesis that early hyperinsulinemia suppresses late hepatic autophagy via the mTOR-dependent transcriptional regulation of autophagy-related genes. The results showed that hyperinsulinemia occurs 3 h after CLP (CLP3h) and is followed by mTOR phosphorylation and autophagy suppression at the late stage (CLP9~15h) of sepsis. The administration of HNMPA, an insulin receptor antagonist, decreases mTOR/ULK-1 (unc-51 like autophagy activating kinase 1) phosphorylation and relieves autophagy suppression in late sepsis. Encapsulated rapamycin, which blocks hepatic mTOR/ULK-1 signaling downstream of insulin, enhances the nuclear translocation of TFEB in early sepsis, increases the protein expression of autophagy-related genes (LC3 and p62) and relieves autophagy suppression in late sepsis. Moreover, rapamycin rescues hepatic dysfunction and increases the survival rate after CLP. These results suggest that early hyperinsulinemia suppresses hepatic autophagy in late sepsis in an mTOR-dependent manner. Nothing to Disclose: LW, PC, YL, CH