TY  - JOUR
AU  - Willemsen, Sam
AU  - Yengej, Fjodor A Yousef
AU  - Puschhof, Jens
AU  - Rookmaaker, Maarten B
AU  - Verhaar, Marianne C
AU  - van Es, Johan
AU  - Beumer, Joep
AU  - Clevers, Hans
TI  - A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 121
IS  - 45
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DKFZ-2024-02211
SP  - e2411189121
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Intestine, Small: metabolism
KW  - Receptors, Cytoplasmic and Nuclear: metabolism
KW  - Receptors, Cytoplasmic and Nuclear: genetics
KW  - Transcriptome
KW  - Receptors, Calcitriol: metabolism
KW  - Receptors, Calcitriol: genetics
KW  - Liver X Receptors: metabolism
KW  - Liver X Receptors: genetics
KW  - Liver X Receptors: agonists
KW  - Organoids: metabolism
KW  - Signal Transduction
KW  - Lipid Metabolism: genetics
KW  - Enterocytes: metabolism
KW  - Pregnane X Receptor: metabolism
KW  - Pregnane X Receptor: genetics
KW  - Gene Expression Regulation: drug effects
KW  - lipid absorption (Other)
KW  - nuclear receptors (Other)
KW  - organoids (Other)
KW  - small intestine (Other)
KW  - Receptors, Cytoplasmic and Nuclear (NLM Chemicals)
KW  - Receptors, Calcitriol (NLM Chemicals)
KW  - Liver X Receptors (NLM Chemicals)
KW  - VDR protein, human (NLM Chemicals)
KW  - Pregnane X Receptor (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39475639
DO  - DOI:10.1073/pnas.2411189121
UR  - https://inrepo02.dkfz.de/record/294378
ER  -