Short-Chain Fatty Acids Stimulate Angiopoietin-Like 4 Synthesis in Human Colon Adenocarcinoma Cells by Activating Peroxisome Proliferator-Activated Receptor gamma

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

128 Citations (Scopus)

Abstract

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 gamma (PPAR gamma), as demonstrated using PPAR gamma antagonist, PPAR gamma knockdown, and transactivation assays, which show activation of PPAR gamma but not PPAR alpha and PPAR delta by SCFA. At concentrations required for PPAR gamma activation and ANGPTL4 induction in colon adenocarcinoma cells, SCFA do not stimulate PPAR gamma in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPAR gamma 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 PPAR gamma. 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
Volume33
Issue number7
DOIs
Publication statusPublished - Apr-2013
Externally publishedYes

Keywords

  • INFLAMMATORY-BOWEL-DISEASE
  • PPAR-GAMMA
  • TRANSCRIPTIONAL ACTIVITY
  • LIPOPROTEIN-LIPASE
  • SKELETAL-MUSCLE
  • GUT MICROBIOTA
  • TARGET GENE
  • EXPRESSION
  • PROTEIN-4
  • BUTYRATE

Cite this