Targeting farnesoid X receptor for liver and metabolic disorders

Fiorucci, Stefano; Rizzo, Gianni; Donini, Annibale; Distrutti, Eleonora; Santucci, Luca

doi:10.1016/j.molmed.2007.06.001

Cited by 186 publications

(172 citation statements)

References 95 publications

Supporting

Mentioning

169

Contrasting

Order By: Relevance

“…Pharmacological activation of FXR was obtained by in vivo and in vitro treatment with 6-ethyl-CDCA (INT-747), a semisynthetic FXR ligand that activates the receptor with an EC 50 of Ϸ 100 nM (21)(22)(23). The efficacy of INT-747 was tested in acute and chronic models of colon inflammation induced by trinitrobenzenesulfonic acid (TNBS) or dextran sulfate (DSS) (24,25).…”

Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

See 1 more Smart Citation

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

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

Self Cite

526

442

View full text Add to dashboard Cite

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.

show abstract

Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

“…TNBS colitis was induced by intrarectal administration of TNBS (0.5 mg/mouse) in 50% ethanol (21,22). Mice receiving TNBS were randomized to receive no treatment or INT-747 at a dose of 5 mg/kg (n ϭ 10 for each group).…”

Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

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

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

Self Cite

526

442

View full text Add to dashboard Cite

show abstract

“…The farnesoid X receptor (FXR; NR1H4) is a member of the nuclear receptor superfamily of ligand-activated regulatory factors (21)(22)(23). Nuclear receptors have been shown to regulate the essential aspect of innate immunity (24 -26) and production of OPN in several experimental settings (27)(28)(29), but this information lacks for FXR.…”

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

Self Cite

144

110

View full text Add to dashboard Cite

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.

show abstract

“…In this context, increased expression of the FXRα gene was consistently observed in the previous and present studies. FXR, which encodes a bile acid sensor, is a key gene involved in bile acid and cholesterol homeostasis, TG metabolism, and inflammation 28 . Bile acids are primarily the endogenous ligands of FXR, and activate the transcription of FXR target genes upon binding to the ligand-binding domain of FXR.…”

Section: Discussionmentioning

confidence: 99%