The role of phosphatidic acid in platelet-derived growth factor–induced proliferation of rat hepatic stellate cells

✍ Scribed by Helen L. Reeves; Mike G. Thompson; Clare L. Dack; Alastair D. Burt; Christopher P. Day

• Publisher: John Wiley and Sons
• Year: 2000
• Tongue: English
• Weight: 143 KB
• Volume: 31
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510310116

✦ Synopsis

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 the lipid-derived second messenger phosphatidic acid (PA) in mediating this effect and, in particular, to determine its interaction with the extracellular signal-regulated kinase (ERK) cascade. HSCs were isolated from rat livers. PA production was determined by lipid extraction and thin-layer chromatography (TLC) after prelabeling cells with [ 3 H]myristate. ERK activity was measured by an in vitro kinase assay after immunoprecipitation. Mitogenic concentrations of PDGF, but not those of the relatively less potent mitogen, transforming growth factor ␣ (TGF-␣), stimulated the sustained production of PA from HSCs. Exogenous PA stimulated HSC proliferation and a sustained increase in ERK activity, and proliferation was completely blocked by the inhibition of ERK activation with PD98059. The stimulation of ERK by PDGF was of a similar magnitude but more sustained than that caused by TGF-␣. These results suggest that the potent mitogenic effect of PDGF in HSCs may be caused, in part, by the generation of PA and subsequently by a more sustained activation of ERK than occurs with less potent mitogens that do not induce the production of this lipid second messenger. (HEPATOLOGY 2000;31:95-100.