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An Nrf2-NF-κB Crosstalk Controls Hepatocyte Proliferation in the Normal and Injured Liver
Andrii Kuklin1, Coenraad Frederik Slabber1, Luigi Tortola1
1Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
Cellular and Molecular Gastroenterology and Hepatology
|February 19, 2025
Summary
Liver regeneration involves Nrf2 and NF-κB. Their crosstalk, particularly with macrophages, is key for hepatocyte proliferation, especially after injury. This study clarifies their combined roles.
Area of Science:
- Hepatology and immunology
- Molecular and cellular biology
- Transcription factor signaling
Background:
- The liver's regenerative and detoxification functions depend on Nrf2 and NF-κB transcription factors.
- While individual roles are known, their interaction in adult liver regeneration is unclear.
Purpose of the Study:
- To investigate the individual and combined roles of Nrf2 and NF-κB (p65) in hepatocyte proliferation.
- To elucidate the crosstalk between these factors and the involvement of macrophages in liver regeneration.
Main Methods:
- Hepatocyte-specific knockout of Nrf2, p65, or both in adult male mice.
- Analysis of liver histology, bile acid profiles, gene expression (RNA-seq), and macrophage depletion.
- Use of AML12 liver cell lines for cell-autonomous and non-cell-autonomous mechanism studies.
Main Results:
- Loss of p65 induced liver inflammation and necrosis; Nrf2 deficiency reduced hepatocyte proliferation.
- Combined Nrf2/p65 deficiency rescued proliferation defects, indicating crosstalk.
- Increased proliferation in double knockouts was non-cell-autonomous, linked to macrophage accumulation.
Conclusions:
- Nrf2 and p65 exhibit crosstalk regulating hepatocyte proliferation.
- Macrophages play a critical role in mediating this Nrf2-p65 dependent liver regeneration.
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