Hepatic ischemia-reperfusion injury is seen in a variety of clinical conditions, including hepatic thrombosis, systemic hypotension, and liver transplantation. Calcium (Ca²⁺) signaling mediates several pathophysiological processes in the liver, but it is not known whether and how intracellular Ca²⁺ channels are involved in the hepatocellular events secondary to ischemia-reperfusion. Using an animal model of hepatic ischemia-reperfusion injury, we observed a progressive increase in expression of the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular Ca²⁺ channel that is not normally expressed in healthy hepatocytes. ITPR3 expression was upregulated, at least in part, by a combination of demethylation of the ITPR3 promoter region and the increased transcriptional activity of the nuclear factor of activated T-cells (NFAT). Additionally, expression of pro-inflammatory interleukins and necrotic surface area were less pronounced in livers of control animals compared to liver-specific ITPR3 KO mice subjected to hepatic damage. Corroborating these findings, ITPR3 expression and activation of NFAT were observed in hepatocytes of liver biopsies from patients who underwent liver ischemia caused by thrombosis after organ transplant. Together, these results are consistent with the idea that ITPR3 expression in hepatocytes plays a protective role during hepatic injury induced by ischemia-reperfusion.

肝缺血再灌注损伤可见于多种临床病症，包括肝血栓形成、全身性低血压和肝移植。钙 (Ca ²⁺ ) 信号传导介导肝脏中的几个病理生理过程，但尚不清楚细胞内 Ca ²⁺通道是否以及如何参与继发于缺血再灌注的肝细胞事件。使用肝缺血再灌注损伤的动物模型，我们观察到肌醇三磷酸受体 (ITPR​​3) 的 3 型同工型的表达逐渐增加，这是一种细胞内 Ca ²⁺正常情况下在健康肝细胞中不表达的通道。ITPR3 表达上调，至少部分是通过 ITPR3 启动子区域的去甲基化和活化 T 细胞 (NFAT) 核因子转录活性增加的组合。此外，与遭受肝损伤的肝脏特异性 ITPR3 KO 小鼠相比，对照动物肝脏中促炎性白细胞介素和坏死表面积的表达不太明显。证实了这些发现，在器官移植后因血栓形成引起肝缺血的患者的肝活检肝细胞中观察到 ITPR3 表达和 NFAT 激活。总之，这些结果与肝细胞中的 ITPR3 表达在缺血再灌注诱导的肝损伤过程中起保护作用的观点一致。