• extracellular signal-regulated kinase;
  • liver fibrosis;
  • p70-S6 kinase;
  • phosphatidylinositol 3-kinase


Background/Aims: Hepatic stellate cells (HSC) play a key role in hepatic fibrogenesis and thus, it is important to understand the intracellular signalling pathways that influence their behaviour. This study investigated the expression and regulation of protein kinase C (PKC) in HSC.

Results: Western blot analysis indicates that rat HSC express at least four PKC isoforms, PKC-α, PKC-δ, PKC-ɛ and PKC-ζ. PKC-α and PKC-ζ were located predominantly in the cytosol and were redistributed to the membrane by the PKC agonist, phorbol 12-myristate 13-acetate (PMA), while PKC-δ and PKC-ɛ were highly membrane-bound and did not undergo translocation by PMA. PKC-α, PKC-δ and PKC-ζ were rapidly downregulated by PMA. However, PKC-ɛ was resistant to downregulation. We also examined phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS), a specific substrate of PKC, as another approach to assess activation of PKC. Platelet-derived growth factor (PDGF) and PMA increased the phosphorylation of MARCKS, suggesting that PDGF can induce PKC activation. PDGF-induced stimulation of extracellular signal-regulated kinase, phosphatidylinositol 3-kinase and p70-S6 kinase was not abrogated by downregulation of PKC-α, PKC-δ and PKC-ζ. Prolonged PKC inhibition did not inhibit the fibrogenic phenotype.

Conclusion: Multiple PKC isoforms are expressed in rat HSC and are differentially regulated by PMA. PDGF activates certain mitogenic signalling pathways independent of PKC-α, PKC-δ and PKC-ζ. Specific PKC isoforms may modulate different cell functions in HSC.