Regulation of fatty acid synthesis by farnesyl pyrophosphate

Shubha Murthy, Huaxiang Tong, Raymond Hohl

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 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. 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.

Original languageEnglish (US)
Pages (from-to)41793-41804
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number51
DOIs
StatePublished - Dec 23 2005

Fingerprint

Mevalonic Acid
Fatty Acids
Terpenes
Biosynthesis
Liver
Sterol Regulatory Element Binding Protein 1
Fatty Acid Synthases
Derivatives
Genes
Chemical activation
Protein Prenylation
Prenylation
Messenger RNA
Ubiquinone
Transcription
farnesyl pyrophosphate
Gene expression
Colon
Epithelial Cells
Cholesterol

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Murthy, Shubha ; Tong, Huaxiang ; Hohl, Raymond. / Regulation of fatty acid synthesis by farnesyl pyrophosphate. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 51. pp. 41793-41804.
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Regulation of fatty acid synthesis by farnesyl pyrophosphate. / Murthy, Shubha; Tong, Huaxiang; Hohl, Raymond.

In: Journal of Biological Chemistry, Vol. 280, No. 51, 23.12.2005, p. 41793-41804.

Research output: Contribution to journalArticle

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