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Akt-mediated foxo1 inhibition is required for liver regeneration
Montse Pauta1,2, Noemi Rotllan2,3,4, Ana Fernández-Hernando2
1Department of Biochemistry and Molecular Genetics, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigaciones Biomédicas en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
Unlabelled:
Understanding the hepatic regenerative process has clinical interest as the effectiveness of many treatments for chronic liver diseases is conditioned by efficient liver regeneration. Experimental evidence points to the need for a temporal coordination between cytokines, growth factors, and metabolic signaling pathways to enable successful liver regeneration. One intracellular mediator that acts as a signal integration node for these processes is the serine-threonine kinase Akt/protein kinase B (Akt). To investigate the contribution of Akt during hepatic regeneration, we performed partial hepatectomy in mice lacking Akt1, Akt2, or both isoforms. We found that absence of Akt1 or Akt2 does not influence liver regeneration after partial hepatectomy. However, hepatic-specific Akt1 and Akt2 null mice show impaired liver regeneration and increased mortality. The major abnormal cellular events observed in total Akt-deficient livers were a marked reduction in cell proliferation, cell hypertrophy, glycogenesis, and lipid droplet formation. Most importantly, liver-specific deletion of FoxO1, a transcription factor regulated by Akt, rescued the hepatic regenerative capability in Akt1-deficient and Akt2-deficient mice and normalized the cellular events associated with liver regeneration.
Conclusion:
The Akt-FoxO1 signaling pathway plays an essential role during liver regeneration.
Insights
The Akt-FoxO1 signaling pathway is crucial for liver regeneration. Deleting FoxO1 in liver cells restored regeneration in mice lacking Akt1 or Akt2, highlighting this pathway's essential role.
Area of Science:
- Hepatology
- Molecular Biology
- Cell Signaling
Background:
- Liver regeneration is vital for treating chronic liver diseases.
- Successful regeneration requires coordinated signaling pathways.
- The serine-threonine kinase Akt (protein kinase B) acts as a key signal integration node.
Purpose of the Study:
- To investigate the role of Akt isoforms (Akt1 and Akt2) in hepatic regeneration.
- To determine the impact of Akt deficiency on liver cell function during regeneration.
Main Methods:
- Partial hepatectomy was performed on mice lacking Akt1, Akt2, or both.
- Hepatic-specific knockout models were used to assess Akt's role.
- The effect of FoxO1 deletion on regeneration was examined in Akt-deficient mice.
Main Results:
- Absence of individual Akt1 or Akt2 isoforms did not impair liver regeneration.
- Mice lacking both Akt1 and Akt2 specifically in the liver showed impaired regeneration and increased mortality.
- Akt deficiency led to reduced cell proliferation, hypertrophy, glycogenesis, and lipid droplet formation.
- Liver-specific deletion of FoxO1 rescued regenerative capacity and normalized cellular events in Akt-deficient mice.
Conclusions:
- The Akt-FoxO1 signaling pathway is essential for effective liver regeneration.
- Targeting the Akt-FoxO1 pathway may offer therapeutic strategies for liver diseases.
