Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration

Abstract

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver regeneration. The aim of this study was to investigate how Nrf2 modulates the cell cycle of replicating hepatocytes in regenerating livers. Wildtype and Nrf2 null mice were subjected to 2/3 partial hepatectomy (PH) and killed at multiple time points for various analyses. Nrf2 null mice exhibited delayed liver regrowth, although the lost liver mass was eventually restored 7 days after PH. Nrf2 deficiency did not affect the number of hepatocytes entering the cell cycle but did delay hepatocyte mitosis. Mechanistically, the lack of Nrf2 resulted in increased mRNA and protein levels of hepatic cyclin A2 when the remaining hepatocytes were replicating in response to PH. Moreover, Nrf2 deficiency in regenerating livers caused dysregulation of Wee1, Cdc2, and cyclin B1 mRNA and protein expression, leading to decreased Cdc2 activity. Thus, Nrf2 is required for timely M phase entry of replicating hepatocytes by ensuring proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration. nuclear factor erythroid 2-related factor 2; hepatocyte mitosis; hepatocyte proliferation NUCLEAR FACTOR ERYTHROID 2-related factor 2 (Nrf2) is a basic leucine zipper region-containing transcription factor that is abundantly expressed in many tissues such as the liver (6). The activity of Nrf2 is regulated by multiple mechanisms, including gene transcription, kelch-like ECH-associated protein 1-mediated proteasome degradation, and kinase-mediated phosphorylation. The sequential events leading to Nrf2 activation include nuclear translocation, heterodimer formation with small Maf portions, binding to an antioxidant response element (ARE), and transactivation of Nrf2 target genes. There are both direct and indirect Nrf2 target genes involved in various cellular functions, including detoxification, metabolism, autophagy, proliferation, differentiation, and apoptosis (3,13,17,26). Previous studies have demonstrated that Nrf2 regulates the hepatocyte proliferative response to liver mass loss (2,33). The aim of the present study was to investigate how Nrf2 modulates the cell cycle progression of replicating hepatocytes during liver repair.Partial hepatectomy (PH) induces highly synchronized entry and progression of the cell cycle in residual hepatocytes. Thus, PH is widely used as an in vivo model to study the regulation of cell proliferation (23). We performed PH on wild-type and Nrf2 null mice and compared the cell cycle progression of replicating hepatocytes. Our data indicate that Nrf2 is a regulator of hepatocyte mitosis.

Clinical implication of Keap1 and phosphorylated Nrf2 expression in hepatocellular carcinoma

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The toxic effects and possible mechanisms of Brusatol on mouse oocytes

“…Of note, recent findings suggest that Nrf2 regulated cell cycle progression by adjusting a series of cyclin[6, 7, 15–17]. Cyclin B1 play an important role on G2/M cell cycle progression.…”

Trk-fused gene (TFG) regulates pancreatic β cell mass and insulin secretory activity

“…Although the precise mechanisms underlying the impaired β-cell proliferation remain unknown, downregulation of Nrf2 activity observed in TFG-depleted β-cells might partly account for the reduced proliferation. A role of Nrf2 in cell proliferation was proposed in a recent review 19 and another report suggested G2/M arrest via Wee1 upregulation to be a cause of delayed liver regeneration in Nrf2-deficient mice 20 . In addition, upregulation of genes involved in the pentose phosphate pathway by Nrf2 has been shown to be a favorable metabolic adaptation to the excessive proliferation of cancer cells 21 .…”