Gamma-linolenic acid suppression of hepatic Ito cell mitogenesis: post-PDGF receptor prostaglandin-independent mechanism

Abstract

Ito cell mitogenesis occurs during liver injury and fibrogenesis in vivo. Platelet-derived-growth factor (PDGF)-induced mitogenesis was studied in cultured rat hepatic Ito cells, which resemble the myofibroblast associated with liver injury. Pretreatment with gamma-linolenic acid (GLA), an essential fatty acid prostanoid precursor, markedly suppressed the PDGF response in a dose-dependent reversible fashion. Prostaglandins E1 and E2 were found to be the predominant prostanoids formed by cultured Ito cells. GLA depressed endogenous PG production, suggesting that the antimitogenic effect was independent of GLA conversion to a prostanoid metabolite. The PDGF-induced cascade was studied with and without GLA to determine the level of regulation that induced the observed suppression. GLA caused no apparent diminution in the abundance of the surface PDGF-beta receptor nor its subsequent activation and tyrosine phosphorylation after PDGF stimulation. Raf kinase activation and Raf perinuclear translocation were also intact despite the presence of GLA. PDGF induction of nuclear Egr and Fos also occurred with or without GLA. Activation of the serine threonine kinase c-Raf has previously been found to be sufficient to activate egr and fos and to induce mitogenesis. Therefore, the GLA suppressive effect is likely to be operative at a parallel non-Raf pathway or distal to Raf-induced early gene expression.