Role of the mTOR/AMPK pathways in metabolic and inflammatory hepatic dysfunction

Sepsis is a medical condition that is distinguished by systemic inflammation and metabolic changes. Host responses to infection, such as cytokine storms and metabolic changes, cause tissue damage. Each organ can adapt to host stress factors at the cellular and tissue level without directly targeting the pathogen and by undergoing various molecular or metabolic changes. We investigated the impact of host factors on hepatocytes in in-vitro cell culture. Pro- inflammatory cytokine mix and lipopolysaccharide (CM & LPS) induced significant cell demise but nutrient restriction in combination with inflammatory stress (S + CM & LPS) protected hepatocytes from damage. mTORC1 activity was reduced in starvation alone but paradoxically increased in combine energy limitation and inflammatory stress. Starvation-based resilience in inflammatory stress diminished in Raptor knockdowns resulting in significantly high cell damage, which was further confirmed by rapamycin-induced mTORC1 pharmacological inhibition. AMPKα along with mTORC1 averts from inflammatory stress damage in nutrient-limited hepatocytes. mTORC1, being a major protein translation regulator, maintained global protein synthesis in starved inflammatory stressed hepatocytes. Protein synthesis was reduced in rapamycin-treated hepatocytes. The assembly of SGs was independent of mTORC1 activity in starvation-based tolerant inflammatory stressed hepatocytes. mTORC1 silencing significantly reduced protein synthesis and intensified autophagy in inflammatory stressed nutrient-limited hepatocytes. Alone inflammatory stress did not induce autophagy even in mTORC1 silenced hepatocytes. In conclusion, our study provides an insight that both mTORC1 and AMPKα activation is essential for the homeostatic activity of stress adaptation mechanisms. Our preliminary data suggest that both mTORC1 and AMPK activity are required for hepatocyte survival and balanced regulation of cellular adaptive responses to sepsis-associated host factors.