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

Akt-mediated foxo1 inhibition is required for liver regeneration.

Author information

1
Department 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.
2
Departments of Medicine and Cell Biology, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY.
3
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.
4
Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine and Department of Pathology, Yale University School of Medicine, New Haven, CT.
5
Edward A. Doisy Department of Biochemistry & Molecular Biology and Center for Cardiovascular Research, Saint Louis University, St. Louis, MO.
6
Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
7
Lilly China Research and Development Center, Shanghai, People's Republic of China.
8
Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clínic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.
9
Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain.

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.

Comment in

PMID:
26473496
PMCID:
PMC5177729
DOI:
10.1002/hep.28286
[Indexed for MEDLINE]
Free PMC Article

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