A comprehensive transcriptome characterization of individual nuclear receptor pathways in the human small intestine

• 成果类型: Article
• 署名作者: Willemsen, Sam; Yengej, Fjodor A. Yousef; Puschhof, Jens; Rookmaaker, Maarten B.; Verhaar, Marianne C.; van Es, Johan; Beumer, Joep; Clevers, Hans
• 署名单位: Royal Netherlands Academy of Arts & Sciences; Hubrecht Institute (KNAW); Utrecht University; Utrecht University Medical Center; Helmholtz Association; German Cancer Research Center (DKFZ); Roche Holding; Princess Maxima Center; Roche Holding
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13892
• DOI: 10.1073/pnas.2411189121
• 发表日期: 2024-11-05
• 关键词: aryl-hydrocarbon receptor; ppar-alpha activation; binding protein; gene-expression; response elements; acid-binding; cell-lines; stem-cells; r package; liver

摘要

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 PPAR alpha 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.