PI‐17

BACKGROUND/AIMS Fatty acid biosynthesis is transcriptionally regulated by liver X receptor (LXR) and sterol regulatory element binding protein‐1c (SREBP‐1c). LXR activation is induced by oxysterol end products of the mevalonate pathway. Whether isoprenoids play a role in regulating the transcription of genes involved in fatty acid biosynthesis is unknown. METHODS CaCo‐2 colon cancer epithelial cells were incubated with lovastatin to deplete mevalonate and its derivatives. This manipulation increased in vitro fatty acid synthesis. RESULTS Mevalonate or farnesyl pyrophosphate (FPP), but not ubiquinone or cholesterol, were effective in reversing the effect. Moreover, the effects of FPP could not be accounted for by protein prenylation, as inhibition of farnesylation did not alter fatty acid synthesis in mevalonate‐depleted cells incubated with the isoprenoid. Fatty acid synthesis in these cells was not altered by inhibition of β‐oxidation. Mevalonate depletion increased fatty acid synthase (FAS) mRNA by transcriptional mechanisms, without increasing gene expression of other enzymes involved in fatty acid biosynthesis or of SREBP‐1c. FPP prevented the increase in FAS mRNA in mevalonate‐depleted cells without altering SREBP‐2 activation. CONCLUSIONS FPP regulates fatty acid synthesis by a mechanism that is likely independent of the SREBP pathway. FPP and select analogues may be a novel approach to altering fatty acid synthesis and the malignant phenotype. Clinical Pharmacology & Therapeutics (2005) 79 , P11–P11; doi: 10.1016/j.clpt.2005.12.038