Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration

Chan, Benjamin KY, Elmasry, Mohamed, Forootan, Shiva S, Russomanno, Giusy ORCID: 0000-0002-3378-5524, Bunday, Tobias M, Zhang, Fang, Brillant, Nathalie, Lewis, Philip J Starkey, Aird, Rhona, Ricci, Emanuele ORCID: 0000-0001-9751-0661
et al (show 14 more authors) (2021) Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration. HEPATOLOGY, 74 (2). pp. 973-986.

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<h4>Background and aims</h4>The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration.<h4>Approach and results</h4>Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients.<h4>Conclusions</h4>Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.

Item Type: Article
Uncontrolled Keywords: Liver, Cells, Cultured, Hepatocytes, Animals, Mice, Knockout, Humans, Mice, Oleanolic Acid, Hepatectomy, Liver Regeneration, Gene Expression Regulation, Adult, Aged, 80 and over, Middle Aged, Female, Male, NF-E2-Related Factor 2, Primary Cell Culture
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate
Depositing User: Symplectic Admin
Date Deposited: 08 Jun 2021 07:29
Last Modified: 18 Jan 2023 22:35
DOI: 10.1002/hep.31859
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