PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy
Lindsey Nicole Jackson
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Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85ƒÑ regulatory and a p110ƒÑ 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 p85ƒÑ and p110ƒÑ 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 p85ƒÑ or p110ƒÑ 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 p85ƒÑ or p110ƒÑ, 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.