Pharmacological Activation of Nrf2 Enhances Functional Liver Regeneration

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. Wild type (WT) and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to partial hepatectomy (PHx). CDDO-Me enhanced the rate of restoration of liver volume and improved liver function (multispectral optoacoustic imaging in wild type, but not Nrf2 null, mice following two-thirds partial hepatectomy. These effects were associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic remodeling in the remnant liver tissue. Overall design: Liver tissues were resected from wild type (WT) mice treated with DMSO or 3 mg/kg CDDO-Me, untreated Nrf2 null (KO) mice, and KO mice treated with 3 mg/kg CDDO-Me (n=4 animals/group). Liver resections were performed 24 hours after the treatments. RNA was isolated and RNA-Seq was performed.