Nuclear factor erythroid 2-like 2 (Nrf2) expression in end-stage liver disease

Kurzawski, Mateusz; Dziedziejko, Violetta; Urasińska, Elżbieta; Post, Mariola; Wójcicki, Maciej; Mietkiewski, J; Droździk, Marek

doi:10.1016/j.etap.2012.03.001

Cited by 24 publications

(21 citation statements)

References 22 publications

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“…By contrast, HCV or HCV proteins were found by another studies 13,14 to induce ROS production and activate Nrf2/ARE pathway, which subsequently protected hepatic cells from oxidative stress. This result is, however, directly contradictory to the findings made in human liver biopsy specimens 15 : Nrf2 expression is evident at a high level in hepatic cells in normal liver but is strikingly repressed in a variety of liver diseases including chronic hepatitis C (CHC). Further in-depth studies are merited to define the exact response and the mechanistic role of Nrf2 directed antioxidant pathway in the pathogenesis of HCV induced liver injury.…”

Section: Introductioncontrasting

confidence: 66%

“…Much of this cytoprotective machinery stems from the Nrf2 antioxidant response pathway, which is the primary cellular defense signaling against the cytotoxic effects of oxidative stress. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (such as kidney and liver) exhibiting highest levels 15 . The high levels of Nrf2 expression by liver cells may protect liver from oxidative stress generated by basal hepatic metabolism or by hepatotoxins or microorganisms.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic targeting of GSK3β enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C

Jiang

Bao

et al. 2014

Gut

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Objective Impaired adaptive response to oxidative injuries is a fundamental mechanism central to the pathogenesis of chronic hepatitis C (CHC). Glycogen synthase kinase (GSK) 3β is an indispensable regulator of the oxidative stress response. However, the exact role of GSK3β in CHC is uncertain and was examined. Design GSK3β and Nrf2 signaling pathways were examined in JFH1 hepatitis C virus (HCV) infected Huh 7.5.1 hepatocytes and also in liver biopsy specimens from CHC patients. Results HCV infection elicited prominent Nrf2 antioxidant response in hepatocytes, marked by elevated expression of the Nrf2 dependent molecule heme oxygenase-1 and subsequent protection from apoptotic cell death. Inhibitory phosphorylation of GSK3β seems to be essential and sufficient for HCV induced Nrf2 response. Mechanistically, GSK3β physically associated and interacted with Nrf2 in hepatocytes. In silico analysis revealed that Nrf2 encompasses multiple GSK3β phosphorylation consensus motifs, denoting Nrf2 as a cognate substrate of GSK3β. In the presence of TGFβ1, the HCV induced GSK3β phosphorylation was blunted via a protein phosphatase 1-dependent mechanism and the cytoprotective Nrf2 response drastically impaired. Lithium, a selective inhibitor of GSK3β, counteracted the effects of TGFβ1. In liver biopsy specimens from CHC patients, the expression of phosphorylated GSK3β positively correlated with Nrf2 expression and was inversely associated with the degree of liver injury. Moreover, CHC patients who received long-term lithium carbonate therapy primarily for concomitant psychiatric disorders exhibited much less liver injury, associated with enhanced hepatic expression of Nrf2. Conclusions Inhibition of GSK3β exerts hepatoprotection in CHC possibly through its direct regulation of Nrf2 antioxidant response.

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Section: Introductioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Therapeutic targeting of GSK3β enhances the Nrf2 antioxidant response and confers hepatic cytoprotection in hepatitis C

Jiang

Bao

et al. 2014

Gut

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“…Therefore, identifying and developing small-molecule Nrf2 activators for disease prevention and intervention have been areas of intensive research. Interestingly, the basal Nrf2 levels were found to be low in aged organisms and certain pathological conditions (Sykiotis and Bohmann 2010;Kurzawski et al 2012). The detailed mechanisms underlying age-and disease-related down-regulation of Nrf2 are unclear, but this knowledge is critical for developing a rational strategy to prevent loss of this major cellular protective response.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of Nrf2 has been shown to confer protection against liver cirrhosis (Kawata et al 2010;Ramani et al 2012;Chen et al 2013). Conversely, compromised Nrf2 signaling and elevation of ROS were detected in end-stage alcoholic liver disease (Kurzawski et al 2012). Although the functional importance of the UPR and Nrf2 responses in liver cirrhosis has recently emerged, the interplay between these two major stress response pathways during the pathogenesis of liver cirrhosis remains unclear.…”

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confidence: 99%

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

et al. 2014

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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. Downregulation 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.

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“…In particular, nuclear factor erythroid-2-related factor 2 (Nrf2) is a key transcription factor for the induction of anti-oxidant enzymes, such as hepatocellular transporters and phase-Ⅱ enzymes, which participate in detoxifi cation and liver regeneration. (1,2) Nrf2 is a basic leucine zipper transcription factor, which was isolated as a member of the nuclear factor erythroid 2 transcription factor family in 1994, and is ubiquitously expressed in various tissues in man. (3) The study by the Yamamoto group demonstrated that Nrf2 forms a heterodimer with small Mafs to induce phase Ⅱ enzymes through antioxidant response elements in the promoter regions of target genes.…”

mentioning

confidence: 99%