Mild hypothermia attenuates hepatic ischemia-reperfusion injury by regulating FoxO1/PPARα pathway

Hepatic ischemia-reperfusion injury (IRI) is a common complication of hepatectomy and liver transplantation. As far as we know, mild hypothermia (MH) is an effective measure to alleviate liver IRI. However, the precise mechanisms have not been fully elucidated. This study investigated the regulatory role of FoxO1/PPARα-mediated energy metabolism in MH-alleviated IRI. Results showed a significant reduction in PPARα expression during liver IRI. Moreover, high PPARα level in post-IR liver specimens correlated with improved liver transplantation outcomes. MH increased blood glucose, elevated gluconeogenesis, and promoted fatty acid oxidation (FAO), indicating a high metabolic state, and also enhanced PPARα expression. Additionally, PPARα promoted FAO and gluconeogenesis, thereby enhancing MH's protective effects on hepatocytes. Mechanistically, MH promoted FoxO1-PPARα interaction, enhancing PCK1 and CPT1a transcription and boosting hepatic metabolism. Selective FoxO1 inhibition by AS1842856 worsened IRI and apoptosis by reducing gluconeogenesis and FAO, MH partially mitigated this damage and promoted energy metabolism. Additionally, through the FoxO1/PPARα pathway, MH inhibits BAX/Cytochrome C/Caspase-3 cascade-initiated apoptosis. Our findings suggest that MH alleviates liver IRI by activating FoxO1/PPARα-mediated energy metabolism and inhibiting the mitochondria-dependent apoptosis pathway, potentially providing a basis for broader MH application.