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

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 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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00858-12.

ACKNOWLEDGMENTS

This study was supported by the Netherlands Nutrigenomics Centre, the Netherlands Organization for Scientific Research (NWO) (VICI grant 700.56.442 to A.B., visitor travel grant 040.11.299 to J.G., and TOP grant 40-00812-98-08030 to S.K.), and the Netherlands Consortium for Systems Biology.

S.A., H.R., S.M., E.K., M.M., G.J.H., and S.K. designed research; S.A., K.L., T.A., J.S.G., E.S., A.K., A.K.H., K.M., D.H., and S.A.-L. performed research; R.H. and B.V.D.B. contributed analytic tools; S.A., K.L., T.A., J.S.G., E.S., A.K., A.K.H., H.R., A.M.J.J.B., E.K., G.J.H., and S.K. analyzed data; S.K. wrote the initial draft of the paper. All authors read and edited the paper.