title: 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-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.
authors.affiliation: Departments of Surgery, Washington University, St Louis, MO 63110, USA. andersonc@wudosis.wustl.edu
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.forename: Gundumi
authors.initials: G
authors.lastname: Upadhya
authors.forename: Kendra D
authors.initials: KD
authors.lastname: Conzen
authors.forename: Jianlou
authors.initials: J
authors.lastname: Jia
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.forename: Sabarinathan
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
authors.forename: William C
authors.initials: WC
authors.lastname: Chapman
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000818:Animals; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D006360:Heat-Shock Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects*; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction; D013312:Stress, Physiological; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014184:Transplantation, Homologous; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051701:Activating Transcription Factor 4; D020169:Caspases; D006360:Heat-Shock Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D013655:Taurochenodeoxycholic Acid; D051742:Transcription Factor CHOP; C497110:Atf4 protein, rat; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C031655:ursodoxicoltaurine; C491071:Casp4 protein, rat