Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colonocytes by selective PPARγ modulation

  • Sheril Alex (Creator)
  • Katja Lange (Creator)
  • Tom Amolo (Creator)
  • Jeffrey S. Grinstead (Creator)
  • Ewa Szalowska (Creator)
  • Arjen Koppen (Creator)
  • Karin Mudde (Creator)
  • Danielle Haenen (Creator)
  • Sa'ad Al-Lahham (Creator)
  • Han Roelofsen (Creator)
  • René Houtman (Creator)
  • Bart van den Burg (Creator)
  • Alexandre M. Bonvin (Creator)
  • Eric Kalkhoven (Creator)
  • Michael Muller (Creator)
  • Guido Hooiveld (Creator)
  • Sander Kersten (Creator)



Angiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as a circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about the mechanisms of regulation of ANGPTL4 in the colon. Here we show that transcription and subsequent secretion of ANGPTL4 in human T84 and HT-29 colonocytes is highly induced by physiological concentrations of products of bacterial fermentation, the short-chain fatty acids. Short-chain fatty acids induce ANGPTL4 by activating the nuclear receptor PPARγ, as shown by microarray, transactivation assays, coactivator peptide recruitment assay, and use of PPARγ antagonist. At concentrations required for PPARγ activation and ANGPTL4 induction in colonocytes, 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 modelling. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes, and 2) SCFA transactivate and bind to PPARγ by serving as selective PPAR modulators. Our data point to activation of PPARγ as a novel mechanism of gene regulation by SCFA in the colon.
Date made available11 Mar 2013
PublisherWageningen University


  • Homo sapiens

Accession numbers

  • GSE40706
  • PRJNA174693

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