title: 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.
authors: Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands.
authors: Sheril
authors: S
authors: Alex
authors: Katja
authors: K
authors: Lange
authors: Tom
authors: T
authors: Amolo
authors: Jeffrey S
authors: JS
authors: Grinstead
authors: Anders K
authors: AK
authors: Haakonsson
authors: Ewa
authors: E
authors: Szalowska
authors: Arjen
authors: A
authors: Koppen
authors: Karin
authors: K
authors: Mudde
authors: Daniëlle
authors: D
authors: Haenen
authors: Sa'ad
authors: S
authors: Al-Lahham
authors: Han
authors: H
authors: Roelofsen
authors: René
authors: R
authors: Houtman
authors: Bart
authors: B
authors: van der Burg
authors: Susanne
authors: S
authors: Mandrup
authors: Alexandre M J J
authors: AM
authors: Bonvin
authors: Eric
authors: E
authors: Kalkhoven
authors: Michael
authors: M
authors: Müller
authors: Guido J
authors: GJ
authors: Hooiveld
authors: Sander
authors: S
authors: Kersten
mesh_terms: D041721:3T3-L1 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D007444:Inulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D005232:Fatty Acids, Volatile; D047495:PPAR gamma; D007444:Inulin