Short chain fatty acids stimulate Angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating PPARy

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 PPARa and PPARd 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.