Akt-mediated foxo1 inhibition is required for liver regeneration

Hepatology. 2016 May;63(5):1660-74. doi: 10.1002/hep.28286. Epub 2015 Dec 18.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / physiology
  • Animals
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / antagonists & inhibitors
  • Forkhead Transcription Factors / physiology*
  • Hepatocytes / pathology
  • Hyperplasia
  • Lipid Metabolism
  • Liver Regeneration*
  • Male
  • Mice
  • Proto-Oncogene Proteins c-akt / physiology*
  • Signal Transduction / physiology

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • 3-Phosphoinositide-Dependent Protein Kinases
  • Akt1 protein, mouse
  • Akt2 protein, mouse
  • Pdpk1 protein, mouse
  • Proto-Oncogene Proteins c-akt