Akt‐mediated foxo1 inhibition is required for liver regeneration

Abstract

Understanding the hepatic regenerative process has clinical interest, since the effectiveness of many treatments for chronic liver diseases is conditioned by an efficient liver regeneration. Experimental evidence points to the need of 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/PKB (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 increase mortality. The major abnormal cellular events observed in total Akt deficient livers were a marked reduction in cell proliferation, cell hypertrophy, glycogenesis and lipid droplets formation. Most importantly, liver-specific deletion of FoxO1, a transcription factor regulated by Akt, rescued the hepatic regenerative capability in Akt1 and Akt2 deficient mice and normalized the cellular events associated with liver regeneration. These results establish an essential role for the Akt-FoxO1 signaling pathway during liver regeneration that has not been previously described.

Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration

“…Transient hepatic steatosis is a characteristic feature of liver regeneration . In other experimental settings, Nampt has been suggested to confer resistance to hepatic steatosis through NAD synthesis, and it was recently shown that NR supplementation confers protection against steatosis in mice fed a high‐fat/high‐sucrose diet .…”

Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation

“…Rictor, interacting with mTOR, was also decreased in METKO+EGFRi mice. Recent studies have shown that AKT activity is essential for full liver regeneration, acting primarily through control and inhibition of Foxo1 . The reduced levels of Rictor–mTORC2 affected AKT activation.…”

PTEN Down‐Regulation Promotes β‐Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice

“…Intriguingly, PI3K seems to promote hyperplasia by phosphorylating signal transducer and activator of transcription 3 (STAT3), whereas the phosphoinositide‐dependent AKT‐mTOR axis stimulates hypertrophic growth . Notably, AKT signaling regulates many of the metabolic adaptations associated with regeneration after tissue loss . No direct evidence supports a role for PTEN in liver regeneration to date.…”