Conserved valproic-acid-induced lipid droplet formation in Dictyostelium and human hepatocytes identifies structurally active compounds
| Autor: | John L. Harwood, Nadine Pawolleck, Irina A. Guschina, Robin S.B. Williams, Heinz Nau, Nick Plant, Daniel Eikel, Leila Chaieb, Lucy M. Elphick |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Neuroscience (miscellaneous)
Medicine (miscellaneous) lcsh:Medicine Models Biological General Biochemistry Genetics and Molecular Biology Dictyostelium discoideum Cell Line chemistry.chemical_compound Immunology and Microbiology (miscellaneous) Species Specificity Lipid droplet Phosphatidylcholine lcsh:Pathology Humans Dictyostelium chemistry.chemical_classification Phosphatidylethanolamine biology Valproic Acid lcsh:R Fatty Acids Fatty acid Lipid metabolism biology.organism_classification Lipid Metabolism Fatty Liver Kinetics Teratogens chemistry Biochemistry Hepatocytes Arachidonic acid lipids (amino acids peptides and proteins) Inositol lcsh:RB1-214 Research Article |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 5, Iss 2, Pp 231-240 (2012) |
| Popis: | SUMMARY Lipid droplet formation and subsequent steatosis (the abnormal retention of lipids within a cell) has been reported to contribute to hepatotoxicity and is an adverse effect of many pharmacological agents including the antiepileptic drug 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 minutes of VPA treatment. Using 3H-labelled polyunsaturated (arachidonic) or saturated (palmitic) fatty acids, we shown that VPA treatment of Dictyostelium gives rise to an increased accumulation of both types of 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 those with high and low lipid-accumulation potential, and validated these activities for effects on lipid droplet formation by 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 could 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 that show liver toxicology. |
| Databáze: | OpenAIRE |
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