NRF2, not always friendly but perhaps misunderstood

Michalopoulos, George K.

doi:10.1002/hep.27090

Cited by 3 publications

(2 citation statements)

References 14 publications

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“…Clearly, Nrf2 activity needs to be tightly controlled during liver regeneration because both overly activated and deficient Nrf2 activity impairs the hepatic regenerative response. The results from studies concerning the roles for Nrf2 in liver regeneration support the notion that Nrf2 functions as "a double-edge sword" in distinct pathological states (24,31).…”

Section: Discussionsupporting

confidence: 58%

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

Zou

Lee

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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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.

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Section: Discussionsupporting

confidence: 58%

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

Zou

Lee

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…As Michalopoulos [ 32 ] notes in reference to Nrf-2 and liver regeneration: “Unexpected and contradictory signaling functions are often discovered, which in retrospect are better understood as providing a fine balance for optimization of processes which the cell understands better than we do. Nrf-2, as an umbrella protector for the hepatocytes, exercises a very important function in perhaps slowing things down, when needed, to prevent complete catastrophe.…”

Section: Discussionmentioning

confidence: 99%

What is Known Regarding the Participation of Factor Nrf-2 in Liver Regeneration?

Morales-González

Madrigal-Santillán

Morales-González

et al. 2015

Cells

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It has been known for years that, after chemical damage or surgical removal of its tissue, the liver initiates a series of changes that, taken together, are known as regeneration, which are focused on the recovery of lost or affected tissue in terms of the anatomical or functional aspect. The Nuclear factor-erythroid 2-related factor (Nrf-2) is a reduction-oxidation reaction (redox)-sensitive transcriptional factor, with the basic leucine Zipper domain (bZIP) motif, encoding the NFE2L2 gene. The Keap1-Nrf2-ARE pathway is transcendental in the regulation of various cellular processes, such as antioxidant defenses, redox equilibrium, the inflammatory process, the apoptotic processes, intermediate metabolism, detoxification, and cellular proliferation. Some reports have demonstrated the regulator role of Nrf-2 in the cellular cycle of the hepatocyte, as well as in the modulation of the antioxidant response and of apoptotic processes during liver regeneration. It has been reported that there is a delay in liver regeneration after Partial hepatectomy (PH) in the absence of Nrf-2, and similarly as a regulator of hepatic cytoprotection due to diverse chemical or biological agents, and in diseases such as hepatitis, fibrosis, cirrhosis, and liver cancer. This regulator/protector capacity is due to the modulation of the Antioxidant response elements (ARE). It is postulated that oxidative stress (OS) can participate in the initial stages of liver regeneration and that Nrf-2 can probably participate. Studies are lacking on the different initiation stages, maintenance, and the termination of liver regeneration alone or with ethanol.

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NF-E2-related factor 2 deletion facilitates hepatic fatty acids metabolism disorder induced by high-fat diet via regulating related genes in mice

Wang

et al. 2016

Food and Chemical Toxicology

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NRF2, not always friendly but perhaps misunderstood

Cited by 3 publications

References 14 publications

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

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

What is Known Regarding the Participation of Factor Nrf-2 in Liver Regeneration?

NF-E2-related factor 2 deletion facilitates hepatic fatty acids metabolism disorder induced by high-fat diet via regulating related genes in mice

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