Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration
| Autor: | Amy Schofield, Philip J. Starkey Lewis, Rhona Aird, Ian M. Copple, Fang Zhang, B. Kevin Park, Christopher E. Goldring, Tobias M Bunday, Stephen W. Fenwick, Yongxiang Fang, Shiva S. Forootan, Harish Poptani, Mohamed Elmasry, Emanuele Ricci, Hassan Malik, Jack Sharkey, Neil R. Kitteringham, Giusy Russomanno, Timothy Andrews, Nathalie Brillant, Benjamin K Y Chan, Adam Lister, Stuart J. Forbes, Rowena Sison-Young |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Genetically modified mouse NF-E2-Related Factor 2 Primary Cell Culture Chronic liver disease Transcriptome Mice medicine Animals Hepatectomy Humans Bardoxolone methyl Oleanolic Acid Transcription factor Cells Cultured Aged 80 and over Mice Knockout Hepatology business.industry Middle Aged medicine.disease Liver regeneration Liver Regeneration medicine.anatomical_structure Gene Expression Regulation Liver Hepatocyte Hepatocytes Cancer research Female Liver function business |
| Zdroj: | Hepatology. 74:973-986 |
| ISSN: | 1527-3350 0270-9139 |
| Popis: | Background and aims 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. Approach and results 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. Conclusions 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. |
| Databáze: | OpenAIRE |
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