Apple-derived extracellular vesicles modulate the expression of human intestinal bile acid transporter ASBT/SLC10A2 via downregulation of transcription factor RARα

Drug Metab Pharmacokinet. 2023 Oct:52:100512. doi: 10.1016/j.dmpk.2023.100512. Epub 2023 Apr 25.


Purpose: Plant-derived extracellular vesicles (EVs) have been reported to exert biological activity on intestinal tissues by delivering their contents into intestinal cells. We previously reported that ASBT/SLC10A2 mRNA was downregulated by apple-derived extracellular vesicles (APEVs). ASBT downregulation is effective in the treatment of cholestasis and chronic constipation, similar to the beneficial effects of apples. Therefore, this study aimed to establish the mechanism of ASBT downregulation by APEVs, focusing on microRNAs present in APEVs.

Results: APEVs downregulated the expression of ASBT, but no significant effect on SLC10A2-3'UTR was observed. Proteomics revealed that APEVs decreased the expression of RARα/NR1B1. The binding of RARα to SLC10A2 promoter was also decreased by APEVs. The stability of NR1B1 mRNA was attenuated by APEVs and its 3'UTR was found to be a target for APEVs. Apple microRNAs that were predicted to interact with NR1B1-3'UTR were present in APEVs, and their mimics suppressed NR1B1 mRNA expression.

Conclusions: Suppression of ASBT by APEVs was indirectly mediated by the downregulation of RARα, and its stability was lowered by microRNAs present in APEVs. This study suggested that macromolecules in food directly affect intestinal function by means of EVs that stabilize them and facilitate their cellular uptake.

Keywords: ASBT; Apple; Bile acid; Extracellular vesicle; Food effect; RARα; microRNA.

MeSH terms

  • 3' Untranslated Regions
  • Bile Acids and Salts
  • Down-Regulation
  • Extracellular Vesicles* / genetics
  • Extracellular Vesicles* / metabolism
  • Humans
  • Malus* / genetics
  • Malus* / metabolism
  • MicroRNAs* / genetics
  • Organic Anion Transporters, Sodium-Dependent / genetics
  • Organic Anion Transporters, Sodium-Dependent / metabolism
  • Symporters* / genetics
  • Symporters* / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Transcription Factors
  • bile acid binding proteins
  • 3' Untranslated Regions
  • Bile Acids and Salts
  • MicroRNAs
  • Symporters
  • Organic Anion Transporters, Sodium-Dependent