TY - JOUR
T1 - A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine
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
PY - 2024/11/5
Y1 - 2024/11/5
N2 - 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.
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 - Transcriptome
KW - Receptors, Calcitriol/metabolism
KW - Liver X Receptors/metabolism
KW - Organoids/metabolism
KW - Signal Transduction
KW - Lipid Metabolism/genetics
KW - Enterocytes/metabolism
KW - Pregnane X Receptor/metabolism
KW - Gene Expression Regulation/drug effects
U2 - 10.1073/pnas.2411189121
DO - 10.1073/pnas.2411189121
M3 - Article
C2 - 39475639
SN - 0027-8424
VL - 121
SP - e2411189121
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -