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The Xenobiotic Receptors CAR and PXR in Health and Disease...
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The Xenobiotic Receptors CAR and PXR in Health and Disease II

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 2790

Special Issue Editors

Dr. William Bourguet

E-Mail Website
Guest Editor
Center for Structural Biochemistry, CNRS UMR5048 / INSERM U1054, 29 rue de Navacelles, 34090 Montpellier, France
Interests: structural biology; protein-protein and protein-ligand interactions; biochemistry; biophysics; nuclear receptors; endocrine disruption
Special Issues, Collections and Topics in MDPI journals
Dr. Patrick Balaguer

E-Mail Website
Guest Editor
Hormonal signaling and cancer, IRCM, INSERM U1194 , 208 rue des apothicaires, 34298 Montpellier, France
Interests: breast and prostate cancer; nuclear receptors; pharmaceutical and environmental nuclear receptors ligands
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The pregnane X receptor (PXR, NR1I2 according to the official nomenclature) and the constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily acting as ligand-dependent transcription factors. They are both highly expressed in the liver and intestine and play pivotal roles in the protection of the body from a variety of harmful endobiotics and xenobiotics by upregulating genes encoding drug-metabolizing enzymes and transporters. Besides their well-documented role in detoxification, mounting experimental evidence suggests that CAR and PXR control many cellular processes including (patho)physiological responses in energy homeostasis, cell proliferation, inflammation, immune response, metabolic disorders, and cancer development. On the other hand, the activation of CAR and PXR has been associated with drug–drug interactions, the deregulation of steroid homeostasis, and chemoresistance. Recent progress in the elucidation of the xenobiotic and non-xenobiotic functions of these receptors can be exploited for further relevant therapeutic applications. This Special Issue of Cells will bring together the most recent advances regarding the various aspects of the action of CAR and PXR, from basic science to applied therapeutic approaches, and will provide new insights into our understanding of these multifaceted nuclear receptors. Original research or review articles are welcome.

Dr. William Bourguet
Dr. Patrick Balaguer
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (2 papers)

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Research

16 pages, 4110 KiB  
Article
CAR Protects Females from Diet-Induced Steatosis and Associated Metabolic Disorders
by Fabiana Oliviero, Wendy Klement, Lucile Mary, Yannick Dauwe, Yannick Lippi, Claire Naylies, Véronique Gayrard, Nicola Marchi and Laila Mselli-Lakhal
Cells 2023, 12(18), 2218; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12182218 - 06 Sep 2023
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Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease worldwide, affecting 70–90% of obese individuals. In humans, a lower NAFLD incidence is reported in pre-menopausal women, although the mechanisms affording this protection remain under-investigated. Here, we tested the [...] Read more.
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease worldwide, affecting 70–90% of obese individuals. In humans, a lower NAFLD incidence is reported in pre-menopausal women, although the mechanisms affording this protection remain under-investigated. Here, we tested the hypothesis that the constitutive androstane nuclear receptor (CAR) plays a role in the pathogenesis of experimental NAFLD. Male and female wild-type (WT) and CAR knock-out (CAR−/−) mice were subjected to a high-fat diet (HFD) for 16 weeks. We examined the metabolic phenotype of mice through body weight follow-up, glucose tolerance tests, analysis of plasmatic metabolic markers, hepatic lipid accumulation, and hepatic transcriptome. Finally, we examined the potential impact of HFD and CAR deletion on specific brain regions, focusing on glial cells. HFD-induced weight gain and hepatic steatosis are more pronounced in WT males than females. CAR−/− females present a NASH-like hepatic transcriptomic signature suggesting a potential NAFLD to NASH transition. Transcriptomic correlation analysis highlighted a possible cross-talk between CAR and ERα receptors. The peripheral effects of CAR deletion in female mice were associated with astrogliosis in the hypothalamus. These findings prove that nuclear receptor CAR may be a potential mechanism entry-point and a therapeutic target for treating NAFLD/NASH. Full article
(This article belongs to the Special Issue The Xenobiotic Receptors CAR and PXR in Health and Disease II)
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15 pages, 3212 KiB  
Article
Okadaic Acid Activates JAK/STAT Signaling to Affect Xenobiotic Metabolism in HepaRG Cells
by Leonie T. D. Wuerger, Felicia Kudiabor, Jimmy Alarcan, Markus Templin, Oliver Poetz, Holger Sieg and Albert Braeuning
Cells 2023, 12(5), 770; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12050770 - 28 Feb 2023
Cited by 3 | Viewed by 1439
Abstract
Okadaic acid (OA) is a marine biotoxin that is produced by algae and accumulates in filter-feeding shellfish, through which it enters the human food chain, leading to diarrheic shellfish poisoning (DSP) after ingestion. Furthermore, additional effects of OA have been observed, such as [...] Read more.
Okadaic acid (OA) is a marine biotoxin that is produced by algae and accumulates in filter-feeding shellfish, through which it enters the human food chain, leading to diarrheic shellfish poisoning (DSP) after ingestion. Furthermore, additional effects of OA have been observed, such as cytotoxicity. Additionally, a strong downregulation of the expression of xenobiotic-metabolizing enzymes in the liver can be observed. The underlying mechanisms of this, however, remain to be examined. In this study, we investigated a possible underlying mechanism of the downregulation of cytochrome P450 (CYP) enzymes and the nuclear receptors pregnane X receptor (PXR) and retinoid-X-receptor alpha (RXRα) by OA through NF-κB and subsequent JAK/STAT activation in human HepaRG hepatocarcinoma cells. Our data suggest an activation of NF-κB signaling and subsequent expression and release of interleukins, which then activate JAK-dependent signaling and thus STAT3. Moreover, using the NF-κB inhibitors JSH-23 and Methysticin and the JAK inhibitors Decernotinib and Tofacitinib, we were also able to demonstrate a connection between OA-induced NF-κB and JAK signaling and the downregulation of CYP enzymes. Overall, we provide clear evidence that the effect of OA on the expression of CYP enzymes in HepaRG cells is regulated through NF-κB and subsequent JAK signaling. Full article
(This article belongs to the Special Issue The Xenobiotic Receptors CAR and PXR in Health and Disease II)
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