Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ

Sheril Alex, Katja Lange, Tom Amolo, Jeffrey S Grinstead, Anders K Haakonsson, Ewa Szalowska, Arjen Koppen, Karin Mudde, Daniëlle Haenen, Sa'ad Al-Lahham, Han Roelofsen, René Houtman, Bart van der Burg, Susanne Mandrup, Alexandre M J J Bonvin, Eric Kalkhoven, Michael Müller, Guido J Hooiveld, Sander Kersten

Research output: Contribution to journalArticlepeer-review

220 Citations (Scopus)


Angiopoietin-like protein 4 (ANGPTL4/FIAF) has been proposed as a circulating mediator between the gut microbiota and fat storage. Here, we show that transcription and secretion of ANGPTL4 in human T84 and HT29 colon adenocarcinoma cells is highly induced by physiological concentrations of short-chain fatty acids (SCFA). SCFA induce ANGPTL4 by activating the nuclear receptor peroxisome proliferator activated receptor γ (PPARγ), as demonstrated using PPARγ antagonist, PPARγ knockdown, and transactivation assays, which show activation of PPARγ but not PPARα and PPARδ by SCFA. At concentrations required for PPARγ activation and ANGPTL4 induction in colon adenocarcinoma cells, SCFA do not stimulate PPARγ in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPARγ modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modeling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin induced PPAR target genes and pathways in the colon. We conclude that (i) SCFA potently stimulate ANGPTL4 synthesis in human colon adenocarcinoma cells and (ii) SCFA transactivate and bind to PPARγ. Our data point to activation of PPARs as a novel mechanism of gene regulation by SCFA in the colon, in addition to other mechanisms of action of SCFA.
Original languageEnglish
Pages (from-to)1303-1316
Number of pages14
JournalMolecular and Cellular Biology
Issue number7
Publication statusPublished - Apr 2013


  • 3T3-L1 Cells
  • Adenocarcinoma
  • Adipogenesis
  • Angiopoietins
  • Animals
  • Cell Line, Tumor
  • Colon
  • Colonic Neoplasms
  • Fatty Acids, Volatile
  • HT29 Cells
  • Humans
  • Inulin
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR gamma
  • Transcription, Genetic
  • Transcriptional Activation

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