PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy

Lindsey N. Jackson, Shawn D. Larson, Scott R. Silva, Piotr G. Rychahou, L. Andy Chen, Suimin Qiu, Srinivasan Rajaraman, B. Mark Evers

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85α regulatory and a p110α catalytic subunit, participates in multiple cellular processes, including cell growth and survival; however, the role of PI3K in liver regeneration has not been clearly delineated. In this study, we used the potent PI3K inhibitor wortmannin and small interfering RNA (siRNA) targeting the p85α and p110α subunits to determine whether total or selective PI3K inhibition would abrogate the proliferative response of the liver after partial hepatectomy in mice. Hepatic resection is associated with an induction in PI3K activity; total PI3K blockade with wortmannin and selective inhibition of p85α or p110α with siRNA resulted in a significant decrease in hepatocyte proliferation, especially at the earliest time points. Fewer macrophages and Kupffer cells were present in the regenerating liver of mice treated with wortmannin or siRNA to p85α or p110α, as reflected by a paucity of F4/80-positive cells. Additionally, PI3K inhibition led to an aberrant architecture in the regenerating hepatocytes characterized by vacuolization, lipid deposition, and glycogen accumulation; these changes were not noted in the sham livers. Our data demonstrate that PI3K/Akt pathway activation plays a critical role in the early regenerative response of the liver after resection; inhibition of this pathway markedly abrogates the normal hepatic regenerative response, most likely by inhibiting macrophage infiltration and cytokine elaboration and thus hepatocyte priming for replication.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume294
Issue number6
DOIs
StatePublished - Jun 2008

Fingerprint

Phosphatidylinositol 3-Kinase
Hepatectomy
Regeneration
Liver
Small Interfering RNA
Hepatocytes
Liver Regeneration
Macrophages
Kupffer Cells
Glycogen
Catalytic Domain
Cell Survival
Cytokines
Lipids

Keywords

  • Autophagy
  • Kupffer cell
  • Liver regeneration
  • Macrophage
  • p110α
  • p85α
  • Phosphatidylinositol 3-kinase
  • Wortmannin

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy. / Jackson, Lindsey N.; Larson, Shawn D.; Silva, Scott R.; Rychahou, Piotr G.; Chen, L. Andy; Qiu, Suimin; Rajaraman, Srinivasan; Evers, B. Mark.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 294, No. 6, 06.2008.

Research output: Contribution to journalArticle

Jackson, Lindsey N. ; Larson, Shawn D. ; Silva, Scott R. ; Rychahou, Piotr G. ; Chen, L. Andy ; Qiu, Suimin ; Rajaraman, Srinivasan ; Evers, B. Mark. / PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2008 ; Vol. 294, No. 6.
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AU - Larson, Shawn D.

AU - Silva, Scott R.

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AU - Chen, L. Andy

AU - Qiu, Suimin

AU - Rajaraman, Srinivasan

AU - Evers, B. Mark

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AB - Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85α regulatory and a p110α catalytic subunit, participates in multiple cellular processes, including cell growth and survival; however, the role of PI3K in liver regeneration has not been clearly delineated. In this study, we used the potent PI3K inhibitor wortmannin and small interfering RNA (siRNA) targeting the p85α and p110α subunits to determine whether total or selective PI3K inhibition would abrogate the proliferative response of the liver after partial hepatectomy in mice. Hepatic resection is associated with an induction in PI3K activity; total PI3K blockade with wortmannin and selective inhibition of p85α or p110α with siRNA resulted in a significant decrease in hepatocyte proliferation, especially at the earliest time points. Fewer macrophages and Kupffer cells were present in the regenerating liver of mice treated with wortmannin or siRNA to p85α or p110α, as reflected by a paucity of F4/80-positive cells. Additionally, PI3K inhibition led to an aberrant architecture in the regenerating hepatocytes characterized by vacuolization, lipid deposition, and glycogen accumulation; these changes were not noted in the sham livers. Our data demonstrate that PI3K/Akt pathway activation plays a critical role in the early regenerative response of the liver after resection; inhibition of this pathway markedly abrogates the normal hepatic regenerative response, most likely by inhibiting macrophage infiltration and cytokine elaboration and thus hepatocyte priming for replication.

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