TY - JOUR
T1 - PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy
AU - Jackson, Lindsey N.
AU - Larson, Shawn D.
AU - Silva, Scott R.
AU - Rychahou, Piotr G.
AU - Chen, L. Andy
AU - Qiu, Suimin
AU - Rajaraman, Srinivasan
AU - Evers, B. Mark
PY - 2008/6
Y1 - 2008/6
N2 - 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.
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.
KW - Autophagy
KW - Kupffer cell
KW - Liver regeneration
KW - Macrophage
KW - Phosphatidylinositol 3-kinase
KW - Wortmannin
KW - p110α
KW - p85α
UR - http://www.scopus.com/inward/record.url?scp=48249122445&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=48249122445&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00062.2008
DO - 10.1152/ajpgi.00062.2008
M3 - Article
C2 - 18388186
AN - SCOPUS:48249122445
SN - 0193-1857
VL - 294
SP - G1401-G1410
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 6
ER -