Farnesyl Pyrophosphate Is a Novel Transcriptional Activator for a Subset of Nuclear Hormone Receptors

Abstract

In silico docking of a chemical library with the ligand-binding domain of thyroid hormone nuclear receptor-beta (TRbeta) suggested that farnesyl pyrophosphate (FPP), a key intermediate in cholesterol synthesis and protein farnesylation, might function as an agonist. Surprisingly, addition of FPP to cells activated TR as well as the classical steroid hormone receptors but not peroxisome proliferative-activating receptors, farnesoid X receptor, liver X receptor, or several orphan nuclear receptors the ligands of which are unknown. FPP enhanced receptor-coactivator binding in vitro and in vivo, and elevation of FPP levels in cells by squalene synthetase or farnesyl transferase inhibitors leads to activation. The FPP effect was blocked by selective receptor antagonists, and in silico docking with 143 nuclear receptor ligand-binding domain structures revealed that FPP only docked with the agonist conformation of those receptors activated by FPP. Our results suggest that certain nuclear receptors maintain a common structural feature that may reflect an action of FPP on an ancient nuclear receptor or that FPP could function as a ligand for one of the many orphan nuclear receptors the ligands of which have not yet been identified. This finding also has potential interesting implications that may, in part, explain the pleotropic effects of statins as well as certain actions of farnesylation inhibitors in cells.

Farnesyl Pyrophosphate Inhibits Epithelialization and Wound Healing through the Glucocorticoid Receptor

“…FPP Activates GR in Primary Keratinocytes-FPP can enter cells in culture and act as a ligand for GR (12). To further confirm that FPP activates GR in human keratinocytes, we used immunocytochemistry to determine the localization of ligandactivated GR.…”

“…Also, the transcriptional activity of GR correlated with the amount of Ser(P) 211 -GR, suggesting that Ser 211 phosphorylation is a biomarker for ligand activated GR in vivo (31,35). Primary human keratinocytes were incubated with either DEX, ZGA (which elevates FPP in cells by blocking its conversion to squalene) (12,27,28), or FPP, which were added to the medium for 24 h. Control cells received no additions or just mevastatin. We also pretreated cells with mevastatin for 2 h and then incubated the cells with ZGA.…”

“…We previously reported that GC-mediated inhibition of epithelialization occurs through a complex molecular mechanism that involves four GR monomers, the arginine methyltransferase CARM1, and ␤-catenin as co-repressors in the context of the keratin 6/16 (K6/16) promoters (7, 9 -11). In addition, in a recent study we have shown that farnesyl pyrophosphate (FPP) can bind to and activate a subset of nuclear hormone receptors including GR (12). This prior study was limited to an analysis of the effect of activation of a Gal4-GR-LBD chimera using transient transfection.…”

“…In addition to effects on cholesterol synthesis, statins can reduce the activity of the small GTP-binding proteins Rho, Ras, and Rac, where proper membrane localization and function are dependent on isoprenylation (26). However, the finding that FPP can act as an agonist for several nuclear hormone receptors including GR may explain, in part, the pleiotropic effects of statins as well as certain actions of farnesylation inhibitors in cells (12).…”

Nonsterol Isoprenoids Activate Human Constitutive Androstane Receptor in an Isoform-Selective Manner in Primary Cultured Mouse Hepatocytes

“…Several nonsterol isoprenoids are known agonists for nuclear receptors, including thyroid hormone receptor (FPP), estrogen receptor (FPP), PPARa (FOH, geranylgeraniol), and PPARg (FPP, FOH, geranylgeraniol) (Takahashi et al, 2002;Das et al, 2007;Goto et al, 2011b;Nagai et al, 2011). In the current study, FOH also induced CYP2B6-PBREM/XREM reporter activity in the presence of either mCAR or hCAR1; however, SQ1 did not increase the interaction of hCAR1 with the hSRC1-RID, suggesting that SQ1's mechanism of CAR activation differs from that of the ligand agonist CITCO.…”