Gene expression studies conducted with mouse models of Huntington's disease (HD) have revealed profound modifications in gene transcription. However, the complexity of in vivo tissue hampers definition of very early transcriptional modifications and does not allow discrimination between cell-autonomous changes and those resulting from intercellular activity processes. To identify early, cell-autonomous transcriptional changes, we compared gene expression profiles of clonal striata-derived cells expressing different N-terminal 548-amino-acid huntingtin fragments (with 26, 67, 105 or 118 glutamines) under the control of a doxycycline-regulated promoter. In these cells, mutant huntingtin did not form aggregates or cause cell death; therefore, the gene expression profiles report transcriptional changes reflecting early pathogenic events. We found that genes involved in cell signaling, transcription, lipid metabolism and vesicle trafficking were affected, in some cases, within 12 hours of mutant protein induction. Interestingly, this study revealed differential expression of a number of genes involved in cholesterol and fatty acid metabolism, suggesting that these metabolic pathways may play a role in HD pathogenesis.