The synthetic vasopressin analogue, terlipressin, has been extensively used in the management of certain complications associated with end-stage liver diseases (ESLDs), however concerns have been raised regarding its impact on liver function due to decreased portal flow. We used mouse nonlethal hepatic ischemia-reperfusion (IR) model to study the effect of terlipressin on liver injury. Unexpectedly, terlipressin administration either prior to lobetic pedicle occlusion or after reperfusion did not worsen the hepatic IR injury, but rather dramatically ameliorated IR-induced liver apoptosis and necrosis. There was also decreased inflammation within the IR lobes, manifested as reduced neutrophil (Ly-6G+) and macrophage (CD68+) infiltration, as well as diminished hepatic MPO activity and proinflammatory gene expression. Furthermore, terlipressin ameliorated apoptosis in HMGB1-/- but not TLR4-/- mouse livers undergone IR, suggesting such hepatoprotective effect is TLR4- but not HMGB1-dependent. Importantly, despite its known effect of visceral vasoconstriction and decreased portal inflow, hemodynamic evaluation of murine hepatic tissue after IR revealed that terlipressin treatment failed to alter the overall hepatic blood flow in comparison to control group. Further studies identified the expression of vasopressin receptor 1 (VR1) on hepatocytes. In isolated hepatocyte hypoxia-reoxygenation model, the active component of terlipressin, lysine vasopressin effectively conferred hepatocytes resistant to oxidative stress induced apoptosis. Mechanistic studies revealed the VR engagement mediated calcium influx and activation of the Wnt-β-catenin-SGK1 pathway, which subsequently circumvented the proapoptotic events driven by FoxO3 and AP-1 mediated transcription of P27 and Bim, thus ameliorated hepatocyte apoptosis; while blockade of this signaling pathway with small molecule compounds targeting VR1 (SR49059), calcium channels (Verapamil) or Wnt/β-catenin (XAV-939) offset such anti-apoptotic effect. Finally, retrospective study of a cohort of patients with ESLDs revealed significantly improved hepatic function after terlipressin treatment. Our study highlights a novel role of hepatocyte vasopressin signaling in protecting liver from IR injury and has practical implications in both hepatic surgery and transplantation.

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