Title

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

Authors

Jeffrey S. Grinstead, Chemistry Department, University of Puget Sound, Tacoma, Washington, USAFollow
Sheril Alex, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands
Katja Lange, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands
Tom Amolo, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands
Anders K. Haakonsson, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
Ewa Szalowska, RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen, the Netherlands
Arjen Koppen, Department of Metabolic and Endocrine Diseases, Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands
Karin Mudde, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands
Daniëlle Haenen, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands
Sa'ad Al-Lahham, Centre for Medical Biomics, University Medical Centre of Groningen, University of Groningen, Groningen, the Netherlands
Han Roelofsen, Centre for Medical Biomics, University Medical Centre of Groningen, University of Groningen, Groningen, the Netherlands
René Houtman, Pamgene International B.V., 's-Hertogenbosch, the Netherlands
Bart van der Burg, BioDetection Systems BV, Amsterdam, the Netherlands
Susanne Mandrup, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
Alexandre M. J. J. Bonvin, Bijvoet Centre for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, the Netherlands
Eric Kalkhoven, Department of Metabolic and Endocrine Diseases, Universitair Medisch Centrum Utrecht, Utrecht, the Netherlands
Michael Müller, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands; Netherlands Nutrigenomics Centre, Top Institute Food and Nutrition, Wageningen, the Netherlands
Guido J. Hooiveld, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands; Netherlands Nutrigenomics Centre, Top Institute Food and Nutrition, Wageningen, the Netherlands
Sander Kersten, Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands; Netherlands Nutrigenomics Centre, Top Institute Food and Nutrition, Wageningen, the Netherlands

Document Type

Article

Publication Date

4-2013

Publication Title

Molecular and Cellular Biology

Department

Chemistry

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 ? (PPAR?), as demonstrated using PPAR? antagonist, PPAR? knockdown, and transactivation assays, which show activation of PPAR? but not PPAR? and PPAR? by SCFA. At concentrations required for PPAR? activation and ANGPTL4 induction in colon adenocarcinoma cells, SCFA do not stimulate PPAR? in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPAR? 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?. 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.

ISSN

0270-7306