Endoplasmic reticulum stress is a mediator of posttransplant injury in severely steatotic liver allografts

Christopher D. Anderson, Gundumi Upadhya, Kendra D. Conzen, Jianlou Jia, Elizabeth M. Brunt, Venkataswarup Tiriveedhi, Yan Xie, Sabarinathan Ramachandran, Thalachallour Mohanakumar, Nicholas O. Davidson, William C. Chapman

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Hepatic steatosis continues to present a major challenge in liver transplantation. These organs have been shown to have increased susceptibility to cold ischemia/reperfusion (CIR) injury in comparison with otherwise comparable lean livers; the mechanisms governing this increased susceptibility to CIR injury are not fully understood. Endoplasmic reticulum (ER) stress is an important link between hepatic steatosis, insulin resistance, and metabolic syndrome. In this study, we investigated ER stress signaling and blockade in the mediation of CIR injury in severely steatotic rodent allografts. Steatotic allografts from genetically leptin-resistant rodents had increased ER stress responses and increased markers of hepatocellular injury after liver transplantation into strain-matched lean recipients. ER stress response components were reduced by the chemical chaperone taurine-conjugated ursodeoxycholic acid (TUDCA), and this resulted in an improvement in the allograft injury. TUDCA treatment decreased nuclear factor kappa B activation and the proinflammatory cytokines interleukin-6 and interleukin-1β. However, the predominant response was decreased expression of the ER stress cell death mediator [CCAAT/enhancer-binding protein homologous protein (CHOP)]. Furthermore, activation of inflammation-associated caspase-11 was decreased, and this linked ER stress/CHOP to proinflammatory cytokine production after steatotic liver transplantation. These data confirm ER stress in steatotic allografts and implicate this as a mediating mechanism of inflammation and hepatocyte death in the steatotic liver allograft.

Original languageEnglish
Pages (from-to)189-200
Number of pages12
JournalLiver Transplantation
Volume17
Issue number2
DOIs
StatePublished - Feb 1 2011

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