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

Morales-González JA, Madrigal-Santillán E, Morales-González Á, Bautista M, Gayosso-Islas E, Sánchez-Moreno C - Cells (2015)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Col. Casco de Santo Tomás, Del. Miguel Hidalgo, México D.F. 11340, Mexico. jmorales101@yahoo.com.mx.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Schematic of the possible participation of nuclear factor-erythroid 2-related factor (Nrf-2) in liver regeneration induced by partial hepatectomy (panel A), and when a toxic administered during liver regeneration (panel B). PHx: partial hepatectomy; APAP: acetaminophen.
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cells-04-00169-f001: Schematic of the possible participation of nuclear factor-erythroid 2-related factor (Nrf-2) in liver regeneration induced by partial hepatectomy (panel A), and when a toxic administered during liver regeneration (panel B). PHx: partial hepatectomy; APAP: acetaminophen.

Mentions: Very few studies have been conducted to investigate the participation of Nrf-2 in the regulation of hepatocyte proliferation during liver regeneration (Figure 1). Zou et al. [21] investigated the role of Nrf-2 as the cell-cycle modulator during regeneration, for which Partial hepatectomy (PH) was carried on Nrf-2- mice, finding that Nrf-2 deficiency did not affect the number of hepatocytes entering the cellular cycle, but rather, gave rise to a delay in hepatocyte mitosis, in addition to the diminution of Cdc2 activity caused by dysregulation of Wee1, Cdc2, and B1 cyclin in its messenger RNA (mRNA) and as well as in the expression of its protein, and also in mRNA levels and in the protein of cyclin A2. These authors concluded that Nrf-2 is required for timely hepatocyte replication by means of adequate regulation of Cyclin A2 and the Wee1/Cdc2/Cyclin B1 pathway during liver regeneration. Similarly, the group of Zou et al. [22] demonstrated that Nrf-2 participates in maintaining newly regenerated hepatocytes in a fully differentiated state by ensuring proper regulation of HNF4α, Akt1, and p70S6K during liver regeneration. On the other hand, Hu et al. [23] investigated how Keap1 modules the redox cycle and the cellular cycle of the hepatocytes during liver regeneration, for which PH is carried out on Keap1 +/− (Keap1 knockdown) mice, reporting that after PH, Keap1 knockdown caused a delay in entry into the S phase, interruption of S phase progression, and the loss of mitotic rhythm in hepatocyte replication, and that these events are associated with the deregulation of c-Met, EGFR, Akt1, p70S6K, cyclin A2, and cyclin B1 in liver regeneration. With this, the authors demonstrated that Keap1 is a potent regulator of the hepatic redox cycle and the cell cycle of the hepatocytes during liver regeneration.


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

Morales-González JA, Madrigal-Santillán E, Morales-González Á, Bautista M, Gayosso-Islas E, Sánchez-Moreno C - Cells (2015)

Schematic of the possible participation of nuclear factor-erythroid 2-related factor (Nrf-2) in liver regeneration induced by partial hepatectomy (panel A), and when a toxic administered during liver regeneration (panel B). PHx: partial hepatectomy; APAP: acetaminophen.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493454&req=5

cells-04-00169-f001: Schematic of the possible participation of nuclear factor-erythroid 2-related factor (Nrf-2) in liver regeneration induced by partial hepatectomy (panel A), and when a toxic administered during liver regeneration (panel B). PHx: partial hepatectomy; APAP: acetaminophen.
Mentions: Very few studies have been conducted to investigate the participation of Nrf-2 in the regulation of hepatocyte proliferation during liver regeneration (Figure 1). Zou et al. [21] investigated the role of Nrf-2 as the cell-cycle modulator during regeneration, for which Partial hepatectomy (PH) was carried on Nrf-2- mice, finding that Nrf-2 deficiency did not affect the number of hepatocytes entering the cellular cycle, but rather, gave rise to a delay in hepatocyte mitosis, in addition to the diminution of Cdc2 activity caused by dysregulation of Wee1, Cdc2, and B1 cyclin in its messenger RNA (mRNA) and as well as in the expression of its protein, and also in mRNA levels and in the protein of cyclin A2. These authors concluded that Nrf-2 is required for timely hepatocyte replication by means of adequate regulation of Cyclin A2 and the Wee1/Cdc2/Cyclin B1 pathway during liver regeneration. Similarly, the group of Zou et al. [22] demonstrated that Nrf-2 participates in maintaining newly regenerated hepatocytes in a fully differentiated state by ensuring proper regulation of HNF4α, Akt1, and p70S6K during liver regeneration. On the other hand, Hu et al. [23] investigated how Keap1 modules the redox cycle and the cellular cycle of the hepatocytes during liver regeneration, for which PH is carried out on Keap1 +/− (Keap1 knockdown) mice, reporting that after PH, Keap1 knockdown caused a delay in entry into the S phase, interruption of S phase progression, and the loss of mitotic rhythm in hepatocyte replication, and that these events are associated with the deregulation of c-Met, EGFR, Akt1, p70S6K, cyclin A2, and cyclin B1 in liver regeneration. With this, the authors demonstrated that Keap1 is a potent regulator of the hepatic redox cycle and the cell cycle of the hepatocytes during liver regeneration.

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Laboratorio Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Col. Casco de Santo Tomás, Del. Miguel Hidalgo, México D.F. 11340, Mexico. jmorales101@yahoo.com.mx.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus