LXRα agonists ameliorates acute rejection after liver transplantation via ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages

IntroductionLiver X receptor alpha (LXR alpha) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an important role in the occurrence and development of AR. Although the activation of LXR has anti-inflammatory effects, the role of LXR alpha in AR after liver transplantation (LT) has not been elucidated.ObjectiveWe aimed to investigate LXR alpha anti-inflammatory and macrophage polarization regulation effects and mechanisms in acute rejection rat models.MethodsLXR alpha anti-inflammatory and liver function protective effects was initially measured in primary Kupffer cells and LT rat models. Subsequently, a flow cytometry assay was used to detect the regulation effect of LXR alpha in macrophage polarization. HE staining, TUNEL and ELISA were used to evaluate the co-treatment effects of TO901317 and tacrolimus on hepatic apoptosis and liver acute rejection after LT.ResultsIn this study, we found that LPS can inhibit the expression of LXR alpha and activate MAPK pathway and PI3K/AKT/mTOR. We also found that LXR alpha agonist (TO901317) could improve liver function and rat survival after LT by activating the level of ABCA1 and inhibiting MAPK. TO901317 could inhibit macrophage M1-polarization by activating PI3K/AKT/mTOR signal pathway to improve the liver lesion of AR rats after liver transplantation. Additionally, co-treatment with TO901317 and tacrolimus more effectively alleviated the damaging effects of AR following LT than either drug alone.ConclusionOur results suggest that the activation of LXR alpha can improve liver function and rat survival after LT by regulate ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages.