Regulation of fatty acid synthesis by farnesyl pyrophosphate.
Fatty acid biosynthesis is transcriptionally regulated by liver X receptor (LXR) and its gene target, sterol regulatory element binding protein-1c (SREBP-1c). LXR activation is induced by oxysterol end products of the mevalonate pathway and is inhibited by the upstream non-sterol isoprenoid, geranylgeranyl pyrophosphate (GGPP). Whether isoprenoids play a role in regulating the transcription of genes involved in fatty acid biosynthesis is unknown. In CaCo-2 colon epithelial cells, depletion of mevalonate and its derivatives, including oxysterol ligands for LXR, increased fatty acid synthesis. Addition of mevalonate or its isoprenoid derivative, farnesyl pyrophosphate (FPP), prevented this increase. The effects of FPP were likely due to itself or its degradation products, because none of its downstream derivatives, GGPP, ubiquinone, or cholesterol, were effective. Moreover, the effects of FPP could not be accounted for by protein prenylation, because inhibition of farnesylation did not alter fatty acid synthesis in mevalonate-depleted cells incubated with the isoprenoid. Neither was fatty acid synthesis in these cells altered by inhibition of beta-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. The abundance of mature SREBP-2 but not SREBP-1 was increased following mevalonate depletion. FPP prevented the increase in FAS mRNA in mevalonate-depleted cells without altering SREBP-2 activation. Thus, FPP regulates fatty acid synthesis by a mechanism that is likely independent of the SREBP pathway.
Murthy
Shubha
S
Department of Internal Medicine and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. murthys@mail.medicine.uiowa.edu
Tong
Huaxiang
H
Hohl
Raymond J
RJ
D001483:Base Sequence; D015153:Blotting, Western; D018938:Caco-2 Cells; D017931:DNA Primers; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D006801:Humans; D008798:Mevalonic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D012717:Sesquiterpenes
D017931:DNA Primers; D005227:Fatty Acids; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; D019308:Palmitic Acid; C004808:farnesyl pyrophosphate; D064429:Fatty Acid Synthases; D008798:Mevalonic Acid