A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine
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| Titel: | A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine |
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| Autoren: | Sam Willemsen, Fjodor A. Yousef Yengej, Jens Puschhof, Maarten B. Rookmaaker, Marianne C. Verhaar, Johan van Es, Joep Beumer, Hans Clevers |
| Weitere Verfasser: | Regenerative Medicine and Stem Cells, Nefro Vasculaire Geneeskunde, MS Nefrologie, Circulatory Health, Cancer, CMM, Hubrecht Institute with UMC |
| Quelle: | Proc Natl Acad Sci U S A |
| Verlagsinformationen: | Proceedings of the National Academy of Sciences, 2024. |
| Publikationsjahr: | 2024 |
| Schlagwörter: | Small/metabolism, Pregnane X Receptor/metabolism, Gene Expression Regulation/drug effects, Receptors, Cytoplasmic and Nuclear, Cytoplasmic and Nuclear/metabolism, Lipid Metabolism/genetics, Receptors, Intestine, Small, Journal Article, Organoids/metabolism, Humans, Receptors, Calcitriol/metabolism, Intestine, Small/metabolism, Enterocytes/metabolism, Liver X Receptors, Liver X Receptors/metabolism, Pregnane X Receptor, Biological Sciences, Receptors, Cytoplasmic and Nuclear/metabolism, Lipid Metabolism, Intestine, Organoids, Enterocytes, Gene Expression Regulation, Calcitriol/metabolism, Receptors, Calcitriol, Transcriptome, Signal Transduction |
| Beschreibung: | Nuclear receptors (NRs) are widely expressed transcription factors that bind small, lipophilic compounds and regulate diverse biological processes. In the small intestine, NRs are known to act as sensors that control transcriptional responses to endogenous and exogenous signals, yet their downstream effects have not been characterized extensively. Here, we investigate the activation of six different NRs individually in human intestinal organoids using small molecules agonists. We observe changes in key enterocyte functions such as lipid, glucose, and amino acid absorption, the regulation of electrolyte balance, and drug metabolism. Our findings reinforce PXR, LXR, FXR, and PPARα as regulators of lipid absorption. Furthermore, known hepatic effects of AHR and VDR activation were recapitulated in the human small intestine. Finally, we identify unique target genes for intestinal PXR activation (ERG28, TMEM97, and TM7SF2), LXR activation (RAB6B), and VDR activation (CA12). This study provides an unbiased and comprehensive transcriptomic description of individual NR pathways in the human small intestine. By gaining a deeper understanding of the effects of individual NRs, we might better harness their pharmacological and therapeutic potential. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2411189121 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/39475639 https://hdl.handle.net/20.500.11755/33631b73-f7ed-48b1-af5e-eeefba3a655f https://pure.knaw.nl/portal/en/publications/33631b73-f7ed-48b1-af5e-eeefba3a655f https://doi.org/10.1073/pnas.2411189121 https://dspace.library.uu.nl/handle/1874/458697 |
| Rights: | CC BY NC ND URL: http://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) . |
| Dokumentencode: | edsair.doi.dedup.....2eb4d5646b3ca93617d7995250dedb3e |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Nuclear receptors (NRs) are widely expressed transcription factors that bind small, lipophilic compounds and regulate diverse biological processes. In the small intestine, NRs are known to act as sensors that control transcriptional responses to endogenous and exogenous signals, yet their downstream effects have not been characterized extensively. Here, we investigate the activation of six different NRs individually in human intestinal organoids using small molecules agonists. We observe changes in key enterocyte functions such as lipid, glucose, and amino acid absorption, the regulation of electrolyte balance, and drug metabolism. Our findings reinforce PXR, LXR, FXR, and PPARα as regulators of lipid absorption. Furthermore, known hepatic effects of AHR and VDR activation were recapitulated in the human small intestine. Finally, we identify unique target genes for intestinal PXR activation (ERG28, TMEM97, and TM7SF2), LXR activation (RAB6B), and VDR activation (CA12). This study provides an unbiased and comprehensive transcriptomic description of individual NR pathways in the human small intestine. By gaining a deeper understanding of the effects of individual NRs, we might better harness their pharmacological and therapeutic potential. |
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| ISSN: | 10916490 00278424 |
| DOI: | 10.1073/pnas.2411189121 |