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. 1997 Sep 30;94(20):10588-93.
doi: 10.1073/pnas.94.20.10588.

The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism

B M Forman  1 , B Ruan, J Chen, G J Schroepfer Jr, R M Evans
Affiliations

The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism

B M Forman et al. Proc Natl Acad Sci U S A. .

Abstract

LXRalpha is an orphan member of the nuclear hormone receptor superfamily that displays constitutive transcriptional activity. We reasoned that this activity may result from the production of an endogenous activator that is a component of intermediary metabolism. The use of metabolic inhibitors revealed that mevalonic acid biosynthesis is required for LXRalpha activity. Mevalonic acid is a common metabolite used by virtually all eukaryotic cells. It serves as a precursor to a large number of important molecules including farnesyl pyrophosphate, geranylgeranyl pyrophosphate, cholesterol, and oxysterols. Inhibition of LXRalpha could be reversed by addition of mevalonic acid and certain oxysterols but not by other products of mevalonic acid metabolism. Surprisingly, the constitutive activity of LXRalpha was inhibited by geranylgeraniol, a metabolite of mevalonic acid. These findings suggest that LXRalpha may represent a central component of a signaling pathway that is both positively and negatively regulated by multiple products of mevalonate metabolism.

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Figures

Figure 1
Figure 1
The LXRα–RXR heterodimer displays constitutive activity. (A) Schematic diagram illustrating the amino acid sequence identity between FXR and LXRα. (B) The LXRα–RXR heterodimer is constitutively active in a cell-based transient transfection assay. CV-1 cells were transfected with the DR4x3 TK-Luc reporter and the indicated expression vectors. Luciferase and β-galactosidase activity were assayed 40 h posttransfection. (C) Constitutive activity is mediated by the LBDs of LXRα and RXR. Cells were transfected with the GAL4 reporter and vectors expressing the GAL4 DBD, the RXRα LBD, and the LBD of LXRα linked to the GAL4-DBD.
Figure 3
Figure 3
Activation of LXRα by-products of MVA metabolism. (A) Schematic illustration of the MVA biosynthetic pathway. (B) LXRα is activated by MVA and oxysterols. Cells were transfected as in Fig. 2 and then treated with 7.5 μM mevastatin in the presence of 200 μM MVA, isopentenol, or dimethylallylol; 50 μM geraniol, farnesol, or squalene; 25 μM lanosterol and Chol; 10 μM 20(S)-OH-Chol or 22(R)-OH-Chol. (C) Activation of LXRα by oxysterols. Cells were transfected with the DR4x3 reporter and an LXR expression vector and then treated with 10 μM of the indicated oxysterol or 100 nM LG268.
Figure 2
Figure 2
The constitutive activity of LXRα–RXR requires MVA biosynthesis. (A) Inhibition of constitutive activity by HMG–CoA reductase inhibitors. CV-1 cells were transfected as in Fig. 1B and treated with 7.5 μM mevastatin, 7.5 μM lovastatin, or 200 μM MVA. (B) MVA is not required for the constitutive activity of Nurr1. Cells were transfected as indicated and then incubated with 7.5 μM mevastatin or 7.5 μM lovastatin. (C) Mevastatin does not inhibit ligand-dependent activation by nuclear hormone receptors. Cells were transfected with TK-Luc-based reporter constructs and receptor expression vectors and then treated with appropriate ligands (100 nM) as follows: CRBPII/hRXRα/LG268; SPP1x3/hVDR/1,25-di-OH-VD3; MLVx2/hTRβ/l-triiodothyronine and DR5x2/hRARα/Am580.
Figure 4
Figure 4
Geranylgeraniol inhibits the constitutive activity of LXRα-RXR. (A) Inhibition of LXRα–RXR by geranylgeraniol. (B) Geranylgeraniol does not inhibit the constitutive activity of Nurr1 or (C) ligand-dependent activation by nuclear receptors. Transient transfections were performed as above followed by exposure of cells to 30–50 μM geranylgeraniol.
Figure 5
Figure 5
Geranylgeranyl-PP inhibits the DNA binding activity of LXRα–RXR. (A) GG-PP inhibits the DNA binding activity of LXRα-RXR complexes. Mobility shift assays were performed as described with 1 μl of LXRα, 0.4 μl of hRXRa, or 1.4 μl of Nurr1 and 17.5 μM GG-PP. (B) Inhibition of DNA binding is specific to GG-PP. Mobility shift assays were performed as in Fig. 5A with the following compounds: 25 μM of each prenyl-PP, 10 μM mevastatin, 200 μM MVA, or 50 μM of each prenyl alcohol.
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References

    1. Mangelsdorf D J, Evans R M. Cell. 1995;83:841–50. - PubMed
    1. Mangelsdorf D J, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans R M. Cell. 1995;83:835–839. - PMC - PubMed
    1. Forman B M, Chen J, Evans R M. Proc Natl Acad Sci USA. 1997;94:4312–4317. - PMC - PubMed
    1. Kliewer S A, Sundseth S S, Jones S A, Brown P J, Wisely G B, Koble C S, Devchand P, Wahli W, Willson T M, Lenhard J M, Lehmann J M. Proc Natl Acad Sci USA. 1997;94:4318–4323. - PMC - PubMed
    1. Forman B M, Tontonoz P, Chen J, Brun R P, Spiegelman B M, Evans R M. Cell. 1995;83:803–812. - PubMed

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