Lipid droplet formation and subsequent steatosis has been reported to contribute to hepatotoxicity and is an adverse effect of many pharmacological agents including the anti-epileptic valproic acid (VPA). In this study, we have developed a simple model system Dictyostelium discoideum to investigate the effects of VPA and related compounds in lipid droplet formation. In mammalian hepatocytes, VPA increases lipid droplet accumulation over a 24 hour period giving rise to liver cell damage, and we show a similar effect in Dictyostelium following 30 minute VPA treatment. Using 3H-labelled poly-unsaturated (arachidonic) or saturated (palmitic) fatty acids, we shown VPA treatment of Dictyostelium gives rise to an increased accumulation of both fatty acids in phosphatidylcholine, phosphatidylethanolamine and non-polar lipids in this time period, with a similar trend observed in Human hepatocytes (Huh7 cells) labelled with 3H-arachidonic acid. In addition, pharmacological inhibition of β-oxidation in Dictyostelium phenocopies fatty acid accumulation, in agreement with data reported in mammalian systems. Using Dictyostelium, we then screened a range of VPA-related compounds to identify compounds with high and low lipid-accumulation potential, and validated these activities for effects on lipid droplet formation using human hepatocytes. Structure-activity relationships for these VPA-related compounds suggest that lipid accumulation is independent of VPA-catalysed teratogenicity and inositol depletion. These results suggest that Dictyostelium may provide both a novel model system for the analysis of lipid droplet formation in human hepatocytes and a rapid method for identifying VPA-related compounds showing liver toxicology.
- Received June 28, 2011.
- Accepted August 29, 2011.
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