title: Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis.
abstract: Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Down-regulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, USA:
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Beixue
authors.initials: B
authors.lastname: Gao
authors.forename: Can
authors.initials: C
authors.lastname: Tan
authors.forename: Naoko
authors.initials: N
authors.lastname: Yagishita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Pak K
authors.initials: PK
authors.lastname: Wong
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C482345:SYVN1 protein, human; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Hrd1; Nrf2; liver cirrhosis