A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis

Goodwin, Bryan; Jones, Stacey A.; Price, Roger R.; Watson, Michael A.; McKee, David D.; Moore, Linda B.; Galardi, Cristin M.; Wilson, Joan G.; Lewis, Michael C.; Roth, Matthew E.; Maloney, Patrick; Willson, Timothy M.; Kliewer, Steven A.

doi:10.1016/s1097-2765(00)00051-4

Cited by 1,705 publications

(1,416 citation statements)

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“…Previous studies have shown that SHP mediates some of the regulatory activities exerted by FXR (33,36,46,47). SHP is an atypical nuclear receptor, lacking a ligand-binding domain.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there is circumstantial evidence to link the activity of FXR to the regulation of bile acid synthesis from cholesterol, providing a link between nutrient absorption and regulation of key steps in the intermediate metabolism. In addition, because bile acids might be toxic for the liver, activation of FXR by natural and synthetic ligands has been shown to prevent bile acid-induced liver toxicity in a variety of rodent models (33)(34)(35)(36)(37)(38)(39). The homeostatic function of FXR in the liver is highlighted by the demonstration that mice harboring a disrupted FXR (FXR Ϫ/Ϫ ) develop spontaneously an array of hepatocellular abnormalities including adenomas and carcinomas.…”

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confidence: 99%

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The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

144

110

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Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR−/− mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.

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“…Previous studies have shown that SHP mediates some of the regulatory activities exerted by FXR (33,36,46,47). SHP is an atypical nuclear receptor, lacking a ligand-binding domain.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

144

110

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“…Subsequently, SHP binds to the liver receptor homolog-1 (LRH-1, NR5A2) which is a potent activator of CYP7A1. This interaction decreases the transcriptional activity of LRH-1 and subsequently -11 -lowers CYP7A1 transcription [72,73]. Surprisingly, bile acids are able to repress Cyp7a1 expression in SHP -/-animals suggesting the presence of redundant mechanisms [74,75].…”

Section: Nuclear Receptor Regulation Of Cholesterol Biosynthesis and mentioning

confidence: 98%

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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“…Upon activation, FXR alters the transcription of target genes by interacting with FXR-responsive elements as a heterodimer with the 9-cis-retinoic acid receptor (14). In liver cells, FXR negatively regulates genes involved in bile acid synthesis and lipidogenesis but enhances the expression/activity of a number of the basolateral transporters required for bile formation and cholesterol and lipid secretion (15). In intestinal epithelial cells, FXR activates the transcription of the intestinal bile acid-binding protein (I-BABP) (16) and fibroblast growth factor 15 (17), with both genes regulating key aspects of liver and intestinal homeostasis.…”

mentioning

confidence: 99%

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

526

442

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The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR−/− mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA; INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-κB dependent-genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR−/− mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-α, and IFN-γ mRNA expression and attenuating disease severity. In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.

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A Regulatory Cascade of the Nuclear Receptors FXR, SHP-1, and LRH-1 Represses Bile Acid Biosynthesis

Cited by 1,705 publications

References 48 publications

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

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

The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

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