Phosphatidylinositol 3-kinase is required for platelet-derived growth factor's actions on hepatic stellate cells

Gastroenterology. 1997 Apr;112(4):1297-306. doi: 10.1016/s0016-5085(97)70144-6.


Background & aims: Platelet-derived growth factor (PDGF) is the most potent mitogen for hepatic stellate cells (HSCs) in vitro. The aim of this study was to investigate the role of phosphatidylinositol 3-kinase (PI 3-K) activation in mediating the biological effects of PDGF on cultured HSCs and its involvement in vivo.

Methods: HSCs were isolated from normal human livers. PI 3-K was assayed on phosphotyrosine or PDGF-receptor immunoprecipitates by in vitro kinase assay.

Results: Incubation of HSCs with PDGF caused a time-dependent increase in PI 3-K activity. Immunoprecipitation of PDGF-alpha and -beta receptors showed that both subunits associate with active PI 3-K in PDGF-stimulated HSCs. Wortmannin, a specific PI 3-K inhibitor, dose-dependently blocked PI 3-K activity induced by PDGF and inhibited DNA synthesis. PDGF (homodimer)-BB also stimulated HSC chemotaxis, which was inhibited by pretreatment with wortmannin. To explore the potential role of PI 3-K in vivo, liver homogenates from rats treated with CCl4 and from control rats were immunoprecipitated with anti-PDGF-beta-receptor antibodies. Liver injury was associated with increased PDGF-beta-receptor autophosphorylation, and greater PI 3-K activity associated with the receptor itself.

Conclusions: This study shows that in cultured HSCs, PI 3-K activation is necessary for both mitogenesis and chemotaxis induced by PDGF and that this pathway is up-regulated during liver injury in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Cell Division / drug effects
  • Cells, Cultured
  • Chemotactic Factors / antagonists & inhibitors
  • Chemotactic Factors / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Isoenzymes / metabolism
  • Liver / cytology
  • Liver / drug effects*
  • Liver / enzymology*
  • Liver Diseases / enzymology
  • Male
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Wortmannin


  • Androstadienes
  • Chemotactic Factors
  • Enzyme Inhibitors
  • Isoenzymes
  • Platelet-Derived Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Receptor Protein-Tyrosine Kinases
  • Wortmannin