Regulation of Fatty Acid Synthesis by Farnesyl Pyrophosphate

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 ␤-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.The biosynthesis of fatty acids and cholesterol are closely related. Enzymes catalyzing the synthesis and metabolism of both lipids are coordinately regulated by the same transcription factors, the sterol regulatory element-binding proteins (SREBPs) 2 and the liver X receptors (LXRs) (1-3). LXRs belong to a superfamily of nuclear hormone receptors that are ligand-activated transcription factors (3). They form obligate heterodimers with retinoid X receptors (RXRs), another member of this receptor family, and subsequently bind to specific response ele-

Quantitative Determination of Geranyl Diphosphate Levels in Cultured Human Cells

“…Using this method, cellular levels of FPP and GGPP have been determined in cultured cells and in animal tissues [19,26]. Importantly, this method is sensitive enough to measure the changes of FPP and GGPP in cultured cells upon treatment with isoprenoid pathway inhibitors [27,28].…”

Liver-Specific Deletion of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Causes Hepatic Steatosis and Death

“…Recently, a decrease in farnesyl pyrophosphate or farnesol has been shown to induce the expression of FAS independently of SREBP1c. 23 The liver of the L-HMGCRKO mice contained increased numbers of TdT-mediated dUTP-nick end labeling-positive cells. Consistent with the apoptotic nature of the cell death, the activity of caspase 3, a final executer of apoptosis which cleaves to induce the release of cytochrome c from mitochondria, was increased in the liver of the L-HMGCRKO mice.…”

The Crystal Structure of Human Geranylgeranyl Pyrophosphate Synthase Reveals a Novel Hexameric Arrangement and Inhibitory Product Binding

“…1A). The latter products include farnesyl pyrophosphate (FPP) 3 and geranylgeranyl pyrophosphate (GGPP), which are precursors for protein prenylation and might serve as nuclear receptor ligands for the receptors farnesoid X receptor or liver X receptor (1,2). The post-transcriptional modification of proteins with isoprenoids consists of farnesylation and geranylgeranylation of proteins with a C-terminal CaaX motif (where a is any aliphatic residue) by protein prenyltransferases (3,4).…”