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Steatosis is a known risk factor in hepatic surgery and it is associated with postoperative morbidity and mortality. Acetylcholine (ACh) is the major neurotransmitter of vagus nerve and it is released as a response to stressful events like trauma or infection. Stress can also activate the HPA axis that drives the production of cortisol. Both cortisol and ACh have been proved beneficial in experimental models of sepsis, liver transplantation or myocardial ischemia, among other pathologies. In this study, we will study the relationship between cortisol and ACh and their effects on regeneration and injury in seatotic livers submitted to partial hepatectomy (PH) under vascular occlusion, a common technique used in hepatic surgery to avoid bleeding.We determined hepatic levels of ACh and its receptors in obese Zucker rats that underwent partial hepatectomy under vascular occlusion. The ACTH-cortisol pathway was pharmacologically modulated and the effects on hepatic injury and regeneration, as well as its underlying mechanisms of action, were evaluated.There is a significant ACh accumulation driven by the administration of cortisol in steatotic livers submitted to PH under vascular occlusion, that consequently leads to an overexpression of a7 nicotinic and M3 muscarinic ACh receptors. However, administration of ACh prior to surgery increases injury and impairs regeneration via M3 mACh receptor. Interestingly, M3 mAChR antagonist, but not a7 nAChR, alone or in combination with cortisol, did confer eprotection against liver damage caused by the surgical procedure and enhanced regeneration. Moreover, administration of ACh reduced PI3K/Akt hepatic expression and consequently reduced levels of markers of oxidative stress, neutrophil accumulation and edema. In consonance with the results presented above, treatment with an M3 mAChR antagonist, but not a7 nAChR, alone or in combination with cortisol, reduced the hepatic levels of these harmful markers as a result of an overexpression of PI3K and pAKT in these steatotic livers. Thus, this indicates a lesser role of a7 nAChR.The reported benefits of cortisol in PH cannot be extrapolated in situations of PH under vascular occlusion in steatotic livers. Cortisol is responsible of the accumulation of acetylcholine in these livers submitted to partial hepatectomy with vascular occlusion. ACh exerts its action through the M3 ACh receptor, as it exacerbates liver damage and oxidative stress and impairs regeneration. Strategies aimed to block cortisol activity in order to block ACh accumulation and/or blockade of M3 mAChR are probably worthwhile to protect steatotic livers and reduce the incidence of postoperative complications following PH under vascular occlusion.