Premium
Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration
Author(s) -
Chan Benjamin K.Y.,
Elmasry Mohamed,
Forootan Shiva S.,
Russomanno Giusy,
Bunday Tobias M.,
Zhang Fang,
Brillant Nathalie,
Starkey Lewis Philip J.,
Aird Rhona,
Ricci Emanuele,
Andrews Timothy D.,
SisonYoung Rowena L.,
Schofield Amy L.,
Fang Yongxiang,
Lister Adam,
Sharkey Jack W.,
Poptani Harish,
Kitteringham Neil R.,
Forbes Stuart J.,
Malik Hassan Z.,
Fenwick Stephen W.,
Park B. Kevin,
Goldring Christopher E.,
Copple Ian M.
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31859
Subject(s) - liver regeneration , regeneration (biology) , hepatocyte , hepatectomy , medicine , transcriptome , liver function , pathology , cancer research , biology , microbiology and biotechnology , gene expression , surgery , biochemistry , gene , resection , in vitro
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.