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Description:
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Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver . Phosphatidylinositol 3 -kinase (PI3K ) , composed of a p85Ñ regulatory and a p110Ñ 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 these studies , I used the potent PI3K inhibitor , wortmannin , and small -interfering RNA (siRNA ) targeting the p85Ñ and p110Ñ subunits to determine if total or selective PI3K inhibition would abrogate the proliferative response of the liver following resection . After partial hepatectomy in mice , there is an increase in PI3K activity ; total PI3K blockade with wortmannin , and selective inhibition of p85Ñ or p110Ñ with siRNA resulted in a significant decrease in hepatocyte proliferation , especially at the earliest timepoints (ie , 48h and 72h ) . Fewer macrophages and Kupffer cells were present in the regenerating liver of mice treated with wortmannin or siRNA to p85Ñ or p110Ñ , as reflected by a paucity of F4 /80+ cells present by immunohistochemistry (IHC ) . Additionally , PI3K inhibition led to an aberrant hepatocyte architecture characterized by vacuolization , lipid deposition , and glycogen accumulation . My 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 , perhaps by inhibiting macrophage infiltration and cytokine elaboration and thus hepatocyte priming for replication . |