Short chain fatty acids induce ANGPTL4 via PPARγ

Angiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about 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 (SCFA). Induction of ANGPTL4 by SCFA cannot be mimicked by the histone deacetylase inhibitor Trichostatin A. SCFA induce ANGPTL4 by activating the nuclear receptor PPARγ, as shown by use of PPARγ antagonist, PPARγ knock-down, and transactivation assay, which shows activation of PPARγ but not PPARα and PPARδ. 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. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin was associated with induction of PPAR target genes and pathways in the colon, as shown by microarray and subsequent gene set enrichment analysis. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes; 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. Mice received a control diet, or a diet supplemented with 10% inulin for 10 days. After an overnight fast colon was removed, epithelial cells were scraped off, and subjected to gene expression profiling.