MRGPRX4 is a bile acid receptor for human cholestatic itch

Yu, Huasheng; Zhao, Tianjun; Liu, Simin; Wu, Qinxue; Johnson, Omar; Wu, Zhaofa; Zhuang, Zihao; Shi, Yao‐Cheng; Peng, Lirong; He, Renxi; Yang, Yong; Sun, Jianjun; Wang, Xiaoqun; Xu, Haifeng; Zeng, Zheng; Zou, Peng; Lei, Xiaoguang; Luo, Wenqin; Li, Yulong

doi:10.7554/elife.48431

Cited by 109 publications

(128 citation statements)

References 47 publications

(72 reference statements)

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“…Consistently, two human Mrgpr family members, X1 and X4, have been demonstrated to mediate itch sensation evoked by chloroquine and cholestasis, respectively (Liu et al, 2009;Meixiong et al, 2019b;Yu et al, 2019). In the olfactory system, each olfactory receptor neuron within the olfactory epithelium only expresses a single odorant receptor.…”

Section: Discussionmentioning

confidence: 87%

Molecular Signature of Pruriceptive MrgprA3+ Neurons

Xing

Chen

Hilley

et al. 2020

Journal of Investigative Dermatology

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Itch, initiated by the activation of sensory neurons, is associated frequently with dermatological diseases. MrgprA3 þ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulation of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here, we performed RNA sequencing of genetically labeled MrgprA3 þ neurons under both naïve and allergic contact dermatitis conditions. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3 þ neurons, suggesting that MrgprA3 þ neurons are a direct neuronal target for histamine and Mrgpr agonists. In addition, PTPN6 and PCDH12 were identified as highly selective markers of MrgprA3 þ neurons. We also discovered that MrgprA3 þ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potential targets for combating itch.

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Section: Discussionmentioning

confidence: 87%

Molecular Signature of Pruriceptive MrgprA3+ Neurons

Xing

Chen

Hilley

et al. 2020

Journal of Investigative Dermatology

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“…Pruritus and increased LDL cholesterol were the most commonly reported adverse events in obeticholic acid clinical studies (10 mg/25 mg oral dose of OCA once daily over a period of 18 months) (Younossi et al, 2019). According to recent paper from Yu. et al (2019) bile acids (including CDCA) can work as natural ligands for human sensory neuron-expressed Mas-related G protein-coupled receptor X4 (MRGPRX4).…”

Section: Discussionmentioning

confidence: 99%

“…et al (2019) bile acids (including CDCA) can work as natural ligands for human sensory neuron-expressed Mas-related G protein-coupled receptor X4 (MRGPRX4). Bile acids or other MRGPRX4 specific agonist induced itch in human subjects, providing a promising cause of OCA induced-pruritus (Meixiong et al, 2019a;Meixiong et al, 2019b;Yu et al, 2019). In addition, whether bile acid receptor TGR5 participates in cholestatic itch in human also remains unclear (Hodge et al, 2013;Cipriani et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Repositioning an Immunomodulatory Drug Vidofludimus as a Farnesoid X Receptor Modulator With Therapeutic Effects on NAFLD

Zhu

et al. 2020

Front. Pharmacol.

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Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disorder, and yet with no pharmacological treatment approved worldwide. The repositioning of old drugs provides a safe approach for drug development. Vidofludimus, an inhibitor for dihydroorotate dehydrogenase (DHODH) for the treatment of autoimmune disorders, is herein uncovered as a novel modulator for farnesoid X receptor (FXR) by biochemical and crystallographic analysis. We further revealed that vidofludimus exerts in vivo therapeutic effects on dextran sodium sulfate (DSS)-induced colitis in an FXR-dependent manner. Notably, vidofludimus also possesses remarkable beneficial effects in reducing NAFLD by targeting FXR, which may represent a unique approach in developing the treatment for NAFLD. Our findings not only reveal a promising template for the design of novel FXR ligands in treating autoimmune disorders, but also uncover a novel therapeutic effect for vidofludimus on NAFLD based on the newly established relationships among drugs, targets, and diseases.

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“…TBS concentrations were significantly lowered by the anion exchange resin colesevelam without being superior to placebo concerning pruritus improvement [37•]. Recently, a new mechanism in which certain bile salt subspecies could induce itch via the sub-receptor X4 of the Mas-related G protein-coupled receptor family (MRGPRs) was proposed by three different research groups [38][39][40]. As no murine orthologue of MRGPRX4 could be identified, this mechanism may be solely relevant in humans or primates.…”

Section: Biliary Componentsmentioning

confidence: 99%

Newer Approaches to the Management of Pruritus in Cholestatic Liver Disease

Düll

Kremer

2020

Curr Hepatology Rep

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Purpose of Review Chronic pruritus represents a burdensome symptom in cholestatic liver disease. This review recommends a stepwise therapeutic approach, alongside with providing information on epidemiology, pathophysiology, and novel drug targets. Recent Findings Current epidemiological data emphasize chronic itch as a major symptom in immune-mediated liver diseases such as primary biliary cholangitis affecting up to 70% of patients with a significant number suffering from long-lasting and severe pruritus. κ-opioid receptor (KOR) agonists, PPAR agonists, and ileal bile acid transporter (IBAT) inhibitors are currently investigated for their anti-pruritic efficacy in clinical trials. Future therapies may target the autotaxin-lysophosphatidic acid-axis or the Mas-related GPCR MRGPRX4. Summary Cholestatic pruritus still remains a challenging symptom for patients and physicians. Using a stepwise approach including cholestyramine, rifampicin, bezafibrate, naltrexone, and sertraline, pruritus is often adequately manageable. KOR agonists and IBAT inhibitors are currently the most promising anti-pruritic drugs for cholestatic pruritus in development.

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MRGPRX4 is a bile acid receptor for human cholestatic itch

Cited by 109 publications

References 47 publications

Molecular Signature of Pruriceptive MrgprA3+ Neurons

Molecular Signature of Pruriceptive MrgprA3+ Neurons

Repositioning an Immunomodulatory Drug Vidofludimus as a Farnesoid X Receptor Modulator With Therapeutic Effects on NAFLD

Newer Approaches to the Management of Pruritus in Cholestatic Liver Disease

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