期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 294, 期 6, 页码 G1401-G1410出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00062.2008
关键词
liver regeneration; phosphatidylinositol 3-kinase; p85 alpha; p110 alpha; wortmannin; Kupffer cell; macrophage; autophagy
资金
- NIA NIH HHS [R37 AG010885, R37 AG010885-16, R37AG10885] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007639-15, T32DK07639, R01 DK048498-13, P01 DK035608, P01DK35608, R01 DK048498, R01DK48498, P01 DK035608-220001, T32 DK007639] Funding Source: Medline
Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85 alpha regulatory and a p110 alpha 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 p85 alpha and p110 alpha 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 p85 alpha or p110 alpha 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 p85 alpha or p110 alpha, 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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