Regulation of cholesterol 7α-hydroxylase gene ( CYP7A1 ) transcription by the liver orphan receptor (LXRα)

Chiang, John Y.L.; Kimmel, Rhonda; Stroup, Diane

doi:10.1016/s0378-1119(00)00518-7

Cited by 338 publications

(229 citation statements)

References 38 publications

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confidence: 97%

“…Hepatic nuclear factor (HNF)4␣ binds to a DR1, and human ␣-fetoprotein transcription factor (FTF; NR5A2) or mouse liver-related homolog (LRH) binds to an overlapping half-site sequence in the BARE-II. HNF4␣ is the only nuclear receptor that is able to stimulate the human CYP7A1 gene; all other factors tested (FTF, COUP-TFII, LXR␣) inhibited the human CYP7A1 gene (2,5,29).Bile acids are known to activate nuclear receptor farnesoid X receptor (FXR; NR1H4), which binds to the inverted repeat (IR1) sequences and induces several genes involved in lipid metabolism (reviewed in Ref. 4).…”

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confidence: 99%

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Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

Li¹,

Chiang²

2005

American Journal of Physiology-Gastrointestinal and Liver Physi

195

179

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-Bile acids, steroids, and drugs activate steroid and xenobiotic receptor pregnane X receptor (PXR; NR1I2), which induces human cytochrome P4503A4 (CYP3A4) in drug metabolism and cholesterol 7␣-hydroxylase (CYP7A1) in bile acid synthesis in the liver. Rifampicin, a human PXR agonist, inhibits bile acid synthesis and has been used to treat cholestatic diseases. The objective of this study is to elucidate the mechanism by which PXR inhibits CYP7A1 gene transcription. The mRNA expression levels of CYP7A1 and several nuclear receptors known to regulate the CYP7A1 gene were assayed in human primary hepatocytes by quantitative real-time PCR (Q-PCR). Rifampicin reduced CYP7A1 and small heterodimer partner (SHP; NR02B) mRNA expression suggesting that SHP was not involved in PXR inhibition of CYP7A1. Rifampicin inhibited CYP7A1 reporter activity and a PXR binding site was localized to the bile acid response element-I. Mammalian two-hybrid assays revealed that PXR interacted with hepatic nuclear factor 4␣ (HNF4␣, NR2A1) and rifampicin was required. Coimmunoprecipitation assay confirmed PXR interaction with HNF4␣. PXR also interacted with peroxisome proliferator-activated receptor ␥ coactivator (PGC-1␣), which interacted with HNF4␣ and induced CYP7A1 gene transcription. Rifampicin enhanced PXR interaction with HNF4␣ and reduced PGC-1␣ interaction with HNF4␣. Chromatin immunoprecipitation assay showed that PXR, HNF4␣, and PGC-1␣ bound to CYP7A1 chromatin, and rifampicin dissociated PGC-1␣ from chromatin. These results suggest that activation of PXR by rifampicin promotes PXR interaction with HNF4␣ and blocks PGC-1␣ activation with HNF4␣ and results in inhibition of CYP7A1 gene transcription. Rifampicin inhibition of bile acid synthesis may be a protective mechanism against drug and bile acid-induced cholestasis.bile acid synthesis; gene regulation; nuclear receptors; peroxisome proliferator-activated receptor ␥ coactivator BILE ACID FEEDBACK INHIBITS bile acid synthesis by inhibiting the transcription of cholesterol 7␣-hydroxylase (CYP3A4), the rate-limiting enzyme in the bile acid biosynthetic pathway. This tightly regulated feedback mechanism is necessary because bile acids are highly toxic and cholesterol is needed for maintaining cellular structure and function. Recent studies (4) have revealed that bile acid feedback has far-reaching impacts on liver metabolism; it not only regulates bile acid synthesis in the digestive system but also regulates cholesterol, lipoprotein, triglyceride, and glucose metabolisms. The discovery that lithocholic acid (LCA) is an endogenous ligand for pregnane X receptor (PXR) suggests that bile acids may also regulate drug metabolism in the liver and intestine by induction of CYP450 enzymes (27, 34). PXR and its human ortholog steroid and xenobiotic receptor (SXR) induce the CYP3A, CYP2B, and CYP2C families of steroid-and drug-metabolizing enzymes in the liver and intestine (17). Despite the high-sequence identity in the ligand-binding domain between human and mouse PXR, they are very differ...

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confidence: 97%

mentioning

confidence: 99%

Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

Li¹,

Chiang²

2005

American Journal of Physiology-Gastrointestinal and Liver Physi

195

179

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“…When activated by oxysterols or other ligands, LXR binds to this DR-4 element and strongly induces CYP7A1 transcription [62,63]. Interestingly, LXR has much less of an effect on hamster and no effect on human CYP7A1 expression [64,65]. This difference might be attributed to a mutation in the DR-4 site in the human CYP7A1 promoter which prevents LXR from binding [64].…”

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confidence: 99%

“…Interestingly, LXR has much less of an effect on hamster and no effect on human CYP7A1 expression [64,65]. This difference might be attributed to a mutation in the DR-4 site in the human CYP7A1 promoter which prevents LXR from binding [64]. The ability of LXR to induce Cyp7a1 in mice and rats makes these animals extremely resistant to a high cholesterol diet whereas other species, including man, rapidly develop hypercholesterolemia under comparable conditions.…”

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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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“…[31,32]. Bile acids activate FXR, which in turn regulates the expression of enzymes involved their synthesis (Cyp7A1 and Cyp8B1) [33,34], through a negative feedback loop. FXR also regulates the expression of several bile-acid transport proteins including BSEP/SPGP [35].…”

Section: How Can Toxic Effects Be Tracked Indirectly?mentioning

confidence: 99%

Illuminating drug discovery with biological pathways

Apic¹,

et al. 2005

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Systems biology promises to impact significantly on the drug discovery process. One of its ultimate goals is to provide an understanding of the complete set of molecular mechanisms describing an organism. Although this goal is a long way off, many useful insights can already come from currently available information and technology. One of the biggest challenges in drug discovery today is the high attrition rate: many promising candidates prove ineffective or toxic owing to a poor understanding of the molecular mechanisms of biological systems they target. A ''systems'' approach can help identify pathways related to a disease and can suggest secondary effects of drugs that might cause these problems and thus ultimately improve the drug discovery pipeline.

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Regulation of cholesterol 7α-hydroxylase gene ( CYP7A1 ) transcription by the liver orphan receptor (LXRα)

Cited by 338 publications

References 38 publications

Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7α-hydroxylase gene transcription

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

Illuminating drug discovery with biological pathways

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