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

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-1b. 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.

ATF6 Mediates a Pro-Inflammatory Synergy Between ER Stress and TLR Activation in the Pathogenesis of Liver Ischemia-Reperfusion Injury

“…C/EBP homologous protein (CHOP) plays a key role in ER stress-induced cellular damage and its genetic deletion attenuated myocardial and brain IRI in vivo (26, 35), as well as hepatocyte death in vitro (36). Alleviation of ER stress by chemical chaperons, therefore, effectively protected organs from IRI (14, 25, 27, 28). Although several studies, including our own, have demonstrated a potential role of ER stress in regulating inflammatory immune response against IR (13, 28, 35), the underlying mechanism was unclear.…”

Endoplasmic Reticulum Stress Is Increased after Spontaneous Labor in Human Fetal Membranes and Myometrium Where It Regulates the Expression of Prolabor Mediators1

“…For example, LPS stimulation in the lungs increased markers of ER stress, inflammatory cytokines and NFKB and HIF1A activity, which were then reduced following 4-PBA treatment [76]. TUDCA also suppressed activation of NFKB and proinflammatory cytokines when administered to treat allograft injury caused associated with liver transplantation [77]. NFKB is an important upstream regulator of proinflammatory cytokines, PTGS2, PGs, and MMP9 [78].…”

Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression

“…We have previously demonstrated the importance of CHOP in cold ischemia and reperfusion injury of the liver [5], and we have demonstrated autophagy as a mediator of ER stressinduced cell death in hepatocytes [6]. The main function of autophagy is to clear unwanted components in the cytoplasm, and it is believed to be beneficial to cell survival.…”