Inositol 1, 4, 5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury. (November 2020)

• Record Type: Journal Article
• Authors: Lima Filho, Antônio Carlos Melo; França, Andressa; Florentino, Rodrigo M.; dos Santos, Marcone Loiola; de Oliveira Lemos, Fernanda; Missiaggia, Dabny Goulart; Fonseca, Roberta Cristelli; Gustavo Oliveira, André; Ananthanarayanan, Meenakshisundaram; Guerra, Mateus T.; de Castro Fonseca, Matheus; Vidigal, Paula Vieira Teixeira; Lima, Cristiano Xavier; Nathanson, Michael H.; Fatima Leite, M.
• Is Part Of: Cell calcium. Volume 91(2020)
• Publication Date: 2020-11
• Subjects: ALT alanine aminotransferase -- AST aspartate aminotransferase -- AVP arginine vasopressin -- Ca2+ calcium -- CAT catalase -- CsA Cyclosporine -- DAB 3, 3′-diaminobenzidine -- HCC hepatocellular carcinoma -- IL interleukins -- IR ischemia-reperfusion -- ITPR3 type 3 inositol 1, 4, 5-trisphosphate receptor -- LSKO liver specific knockout -- NFAT nuclear factor of activated T-cells -- NAFLD nonalcoholic fatty liver disease -- NASH nonalcoholic steatohepatitis -- SOD-1 superoxide dismutase 1; Calcium signaling -- Nuclear factor of activated T-cells -- Necrosis -- Hepatocytes -- Transplantation; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2020.102264
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: There is de novo expression of ITPR3 in hepatocytes after hepatic ischemia reperfusion. Hypoxia induced by hepatic ischemia-reperfusion activates NFAT, which leads to ITPR3 expression. ITPR3 may play a protective role in hepatocytes after hepatic ischemia-reperfusion. ITPR3 also is expressed in human hepatocytes after ischemia induced by thrombosis. Abstract: Hepatic ischemia-reperfusion injury is seen in a variety of clinical conditions, including hepatic thrombosis, systemic hypotension, and liver transplantation. Calcium (Ca 2+ ) signaling mediates several pathophysiological processes in the liver, but it is not known whether and how intracellular Ca 2+ 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 Ca 2+ 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.