Abstract
Introduction: Post-hepatectomy liver failure (PHLF; 10% incidence) remains a risk following major liver resections. Two-stage surgeries attempt to address the inadequate future liver remnant but with inherent risks. Pharmacological enhancement of liver regeneration could improve outcomes and extend resectability. The transcription factor Nrf2 regulates a battery of metabolic and cell defence genes. We hypothesized that Nrf2 activation would enhance liver regeneration following hepatectomy. Methods: The effects of an Nrf2 activator were evaluated in a mouse major hepatectomy model. Liver volume and function (indocyanine green clearance) were assessed using magnetic resonance imaging and multispectral optoacoustic tomography, respectively. Hepatocyte size was assessed through phalloidin immunofluorescence tissue staining. RNASeq and RT-qPCR were used to determine gene expression changes in mouse liver tissue and primary human hepatocytes. Results: Nrf2 activation significantly enhanced post-hepatectomy regeneration of liver volume and reduced the loss of hepatic function in mice. This was associated with a significant increase in hepatocyte hypertrophy during early regeneration. RNASeq revealed that Nrf2 activation caused an upregulation of redox, cofactor and glutathione metabolism genes, congruent with increases in NADP/H content and glutathione levels, as well as the downregulation of lipid synthesis genes (Figure 1). Notably, such genes were similarly modulated in primary human hepatocytes following in vitro treatment with the Nrf2 activator. Conclusions: Nrf2 activation can improve liver regeneration by enhancing metabolic remodelling and hepatocyte hypertrophy, which translates into an improvement in hepatic function. Our results suggest Nrf2 as a novel target in the treatment of liver pathology, especially the avoidance of PHLF.
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