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Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation.
Digoxin improves steatohepatitis with differential involvement of liver cell subsets in mice through inhibition of PKM2 transactivation. American journal of physiology. Gastrointestinal and liver physiology Zhao, P., Han, S., Arumugam, S., Yousaf, M. N., Qin, Y., Jiang, J. X., Torok, N. J., Chen, Y., Mankash, M. S., Liu, J., Li, J., Iwakiri, Y., Ouyang, X. 2019Abstract
T The cardiac glycoside digoxin was identified as a potent suppressor of PKM2-HIF-1a pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin by the clinically relevant oral route to reduce non-alcoholic steatohepatitis (NASH) in mice and analyzed the cellular basis for this effect with differential involvement of liver cell subsets. C57BL/6J male mice were placed on a high fat diet (HFD) for 10 weeks and started concurrently with the gavage of digoxin (2.5, 0.5, 0.125 mg/kg twice a week) for 5 weeks. Digoxin significantly reduced HFD-induced hepatic damage, steatosis and liver inflammation across a wide dosage range. The lowest dose of digoxin (0.125 mg/kg) showed significant protective effects against liver injury and sterile inflammation. Consistently, digoxin attenuated HIF-1a sustained NLRP3 inflammasome activation in macrophages. We have reported for the first time that PKM2 is up-regulated in hepatocytes with hepatic steatosis and digoxin directly improved hepatocyte mitochondrial dysfunction and steatosis. Mechanistically, digoxin directly bound to PKM2 and inhibited PKM2 targeting HIF-1a transactivation without affecting PKM2 enzyme activation. Thus, oral digoxin showed potential to therapeutically inhibit liver injury in NASH through the regulation of PKM2-HIF1a pathway activation with involvement of multiple cell types. Due to the large clinical experience with oral digoxin this may have significant clinical applicability in human NASH.
View details for DOI 10.1152/ajpgi.00054.2019
View details for PubMedID 31411894