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

Forman, Barry M.; Ruan, Benfang; Chen, Jasmine; Schroepfer, George J.; Evans, Ronald M.

doi:10.1073/pnas.94.20.10588

Cited by 262 publications

(214 citation statements)

References 43 publications

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“…Interestingly, geranylgeranyl-pyrophosphate, another intermediate in mevalonate metabolism to cholesterol, inhibits LXR activity and thus also results in lower CYP7A1 levels [71].…”

Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis and mentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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Cloning and characterization of the orphan nuclear receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) led to major breakthroughs in studying drug-mediated transcriptional induction of drugmetabolizing cytochromes P450 (CYP). More recently, additional roles for CAR and PXR have been discovered. As examples, these xenosensors are involved in the homeostasis of cholesterol, bile acids, bilirubin and other endogenous hydrophobic molecules in the liver: CAR and PXR thus form an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the cholesterol-sensing liver X receptor (LXR, NR1H2/3) and the bileacid-activated farnesoid X receptor (FXR, NR1H4). In this review, functional interactions between these nuclear receptors as well as the consequences on physiology and pathophysiology of the liver are discussed.Key Words: nuclear receptors; drug-induction; lipids; bile acids; cholesterol; CAR; PXR; LXR; FXR; cytochrome P450 -4 -Metabolism of drugs and other xenobiotics in the liver is our body's primary defense against accumulation of potentially toxic, lipophilic compounds. The superfamily of cytochromes P450 (CYPs) are the best-studied class of enzymes in this task [1]. Transcriptional and post-transcriptional regulation of CYPs after exposure to certain drugs or other xenobiotics has been described several decades ago. Classically, the barbiturate phenobarbital induces its own metabolism and excretion by elevating CYP levels [2]. However, the molecular mechanisms underlying this observation remained a conundrum until the discovery and subsequent characterization of the constitutive androstane receptor (CAR, official nomenclature NR1I3) and the pregnane X receptor (PXR, NR1I2, alternatively called PAR or SXR), two members of the superfamily of nuclear receptors [3][4][5][6][7]. Mice with genetic ablations of CAR and PXR have significantly reduced inducibility of CYPs by a variety of drugs [8,9]. Whereas these two receptors share some common ligands and also have an overlapping target gene pattern [10][11][12][13], the mode of activation for CAR and PXR is quite different [14]. PXR is located in the nucleus, it has a low basal activity and is highly activated upon ligand binding [14,15]. In contrast, in the non-induced state, CAR resides in the cytoplasm. After treatment with activators such as phenobarbital, CAR shuttles to the nucleus to activate its target genes. Moreover, CAR localization and activity is regulated by various protein phosphorylation events [16][17][18]. For a more detailed discussion of CAR and PXR functions in drug-mediated induction of CYPs, see some recent reviews (e.g. refs. [19-23] and references therein).-5 - The nuclear receptor NR1I group includes xenosensors and lipid-sensing membersCompounds that induce transcription of CYPs and that activate CAR and PXR are structurally very diverse [21]. However, most of them are small in size and are highly lipophilic [24]. Whereas the CAR ligand-binding domain stru...

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“…Interestingly, geranylgeranyl-pyrophosphate, another intermediate in mevalonate metabolism to cholesterol, inhibits LXR activity and thus also results in lower CYP7A1 levels [71].…”

Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis and mentioning

confidence: 99%

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Handschin¹,

Meyer²

2005

Archives of Biochemistry and Biophysics

156

105

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“…Oxysterols are natural ligands for LXR [3][4][5][6]. A few non-steroidal synthetic LXR agonists have been developed, including T0901317 [7] and GW3965 [8].…”

Section: Introductionmentioning

confidence: 99%

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

Chuu

Chen

Hiipakka

et al. 2007

Biochemical and Biophysical Research Communications

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T0901317 is a potent non-steroidal synthetic liver X receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein expression of prostate specific antigen (PSA), a target gene of androgen receptor (AR) without affecting gene and protein expression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroxyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells.

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“…In the cholesterol biosynthesis pathway, four products, ie squalene, lanosterol, desmosterol and cholesterol, were added to the culture medium at concentrations between 0.1 and 200 m. [17][18][19] None of these compounds were able to block cytotoxicity induced by lovastatin ( Figure 2b). Other mevalonate metabolites that had no protective effects on lovastatininduced cytotoxicity, included dolichol or dolichol phosphate (1-100 g/ml; Figure 2c), ubiquinone (1-50 m; Figure 2d), or isopentenyladenine (1-200 g/ml; Figure 2e).…”

Section: Mva or Ggpp Abrogate Lovastatin-induced Cytotoxicity In Aml-mentioning

confidence: 99%

Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells

et al. 2001

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Lovastatin is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the major regulatory enzyme of the mevalonate pathway. We have previously reported that lovastatin induces a significant apoptotic response in human acute myeloid leukemia (AML) cells. To identify the critical biochemical mechanism(s) essential for lovastatin-induced apoptosis, add-back experiments were conducted to determine which downstream product(s) of the mevalonate pathway could suppress this apoptotic response. Apoptosis induced by lovastatin was abrogated by mevalonate (MVA) and geranylgeranyl pyrophosphate (GGPP), and was partially inhibited by farnesyl pyrophosphate (FPP). Other products of the mevalonate pathway including cholesterol, squalene, lanosterol, desmosterol, dolichol, dolichol phosphate, ubiquinone, and isopentenyladenine did not affect lovastatininduced apoptosis in AML cells. Our results suggest that inhibiting geranylgeranylation of target proteins is the predominant mechanism of lovastatin-induced apoptosis in AML cells. In support of this hypothesis, the geranylgeranyl transferase inhibitor (GGTI-298) mimicked the effect of lovastatin, whereas the farnesyl transferase inhibitor (FTI-277) was much less effective at triggering apoptosis in AML cells. Inhibition of geranylgeranylation was monitored and associated with the apoptotic response induced by lovastatin and GGTI-298 in the AML cells. We conclude that blockage of the mevalonate pathway, particularly inhibition of protein geranylgeranylation holds a critical role in the mechanism of lovastatin-induced apoptosis in AML cells. Leukemia (2001Leukemia ( ) 15, 1398Leukemia ( -1407

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

Cited by 262 publications

References 43 publications

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells

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