Dataset Information

Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling.

ABSTRACT:

Background & aims

In cholestatic syndromes, body accumulation of bile acids is thought to cause itching. However, the mechanisms supporting this effect remain elusive. Recently, GPBAR1 (TGR5) a G-protein coupled receptor has been shown to mediate itching caused by intradermal administration of DCA and LCA. 6?-ethyl-3?, 7?-dihydroxy-24-nor-5?-cholan-23-ol (BAR502) is a non-bile acid dual ligand for FXR and GPBAR1.

Methods

Cholestasis was induced in wild type and GPBAR1-/- mice by administration of ?-naphthyl-isothiocyanate (ANIT) or 17?-ethynylestradiol.

Results

In naïve mice skin application of DCA, TLCA, 6-ECDCA, oleanolic and betulinic acid induces a GPBAR1 dependent pruritogenic response that could be desensitized by re-challenging the mice with the same GPBAR1 agonist. In wild type and GPBAR1-/- mice cholestasis induced by ANIT fails to induce spontaneous itching and abrogates scratching behavior caused by intradermal administration of DCA. In this model, co-treatment with BAR502 increases survival, attenuates serum alkaline phosphatase levels and robustly modulates the liver expression of canonical FXR target genes including OST?, BSEP, SHP and MDR1, without inducing pruritus. Betulinic acid, a selective GPBAR1 ligand, failed to rescue wild type and GPBAR1-/- mice from ANIT cholestasis but did not induced itching. In the 17?-ethynylestradiol model BAR502 attenuates cholestasis and reshapes bile acid pool without inducing itching.

Conclusions

The itching response to intradermal injection of GPBAR1 agonists desensitizes rapidly and is deactivated in models of cholestasis, explain the lack of correlation between bile acids levels and itching severity in cholestatic syndromes. In models of non-obstructive cholestasis, BAR502 attenuates liver injury without causing itching.

SUBMITTER: Cipriani S

PROVIDER: S-EPMC4503431 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling.

Cipriani Sabrina S Renga Barbara B D'Amore Claudio C Simonetti Michele M De Tursi Antonio Angelo AA Carino Adriana A Monti Maria Chiara MC Sepe Valentina V Zampella Angela A Fiorucci Stefano S

PloS one 20150715 7

<h4>Background & aims</h4>In cholestatic syndromes, body accumulation of bile acids is thought to cause itching. However, the mechanisms supporting this effect remain elusive. Recently, GPBAR1 (TGR5) a G-protein coupled receptor has been shown to mediate itching caused by intradermal administration of DCA and LCA. 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (BAR502) is a non-bile acid dual ligand for FXR and GPBAR1.<h4>Methods</h4>Cholestasis was induced in wild type and GPBAR1-/- mice by a ...[more]

PMID: 26177448

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Dataset Information

Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling.

Background & aims

Methods

Results

Conclusions

Publications

Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling.

Similar Datasets

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