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024 7 _ |a 10.1073/pnas.2411189121
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037 _ _ |a DKFZ-2024-02211
041 _ _ |a English
082 _ _ |a 500
100 1 _ |a Willemsen, Sam
|b 0
245 _ _ |a A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine.
260 _ _ |a Washington, DC
|c 2024
|b National Acad. of Sciences
336 7 _ |a article
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336 7 _ |a Journal Article
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520 _ _ |a 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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650 _ 7 |a lipid absorption
|2 Other
650 _ 7 |a nuclear receptors
|2 Other
650 _ 7 |a organoids
|2 Other
650 _ 7 |a small intestine
|2 Other
650 _ 7 |a Receptors, Cytoplasmic and Nuclear
|2 NLM Chemicals
650 _ 7 |a Receptors, Calcitriol
|2 NLM Chemicals
650 _ 7 |a Liver X Receptors
|2 NLM Chemicals
650 _ 7 |a VDR protein, human
|2 NLM Chemicals
650 _ 7 |a Pregnane X Receptor
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Intestine, Small: metabolism
|2 MeSH
650 _ 2 |a Receptors, Cytoplasmic and Nuclear: metabolism
|2 MeSH
650 _ 2 |a Receptors, Cytoplasmic and Nuclear: genetics
|2 MeSH
650 _ 2 |a Transcriptome
|2 MeSH
650 _ 2 |a Receptors, Calcitriol: metabolism
|2 MeSH
650 _ 2 |a Receptors, Calcitriol: genetics
|2 MeSH
650 _ 2 |a Liver X Receptors: metabolism
|2 MeSH
650 _ 2 |a Liver X Receptors: genetics
|2 MeSH
650 _ 2 |a Liver X Receptors: agonists
|2 MeSH
650 _ 2 |a Organoids: metabolism
|2 MeSH
650 _ 2 |a Signal Transduction
|2 MeSH
650 _ 2 |a Lipid Metabolism: genetics
|2 MeSH
650 _ 2 |a Enterocytes: metabolism
|2 MeSH
650 _ 2 |a Pregnane X Receptor: metabolism
|2 MeSH
650 _ 2 |a Pregnane X Receptor: genetics
|2 MeSH
650 _ 2 |a Gene Expression Regulation: drug effects
|2 MeSH
700 1 _ |a Yengej, Fjodor A Yousef
|b 1
700 1 _ |a Puschhof, Jens
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700 1 _ |a Rookmaaker, Maarten B
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700 1 _ |a Verhaar, Marianne C
|0 0000-0002-3276-6428
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700 1 _ |a van Es, Johan
|b 5
700 1 _ |a Beumer, Joep
|b 6
700 1 _ |a Clevers, Hans
|0 0000-0002-3077-5582
|b 7
773 _ _ |a 10.1073/pnas.2411189121
|g Vol. 121, no. 45, p. e2411189121
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|p e2411189121
|t Proceedings of the National Academy of Sciences of the United States of America
|v 121
|y 2024
|x 0027-8424
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