Document Detail

Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ.
MedLine Citation:
PMID:  23339868     Owner:  NLM     Status:  MEDLINE    
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.
Sheril Alex; Katja Lange; Tom Amolo; Jeffrey S Grinstead; Anders K Haakonsson; Ewa Szalowska; Arjen Koppen; Karin Mudde; Daniëlle Haenen; Sa'ad Al-Lahham; Han Roelofsen; René Houtman; Bart van der Burg; Susanne Mandrup; Alexandre M J J Bonvin; Eric Kalkhoven; Michael Müller; Guido J Hooiveld; Sander Kersten
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-22
Journal Detail:
Title:  Molecular and cellular biology     Volume:  33     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-11     Completed Date:  2013-07-30     Revised Date:  2013-10-08    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1303-16     Citation Subset:  IM    
Nutrition, Metabolism and Genomics Group, Wageningen University, Wageningen, the Netherlands.
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MeSH Terms
3T3-L1 Cells
Adenocarcinoma / genetics,  metabolism*
Adipogenesis / genetics
Angiopoietins / biosynthesis*,  genetics,  metabolism
Cell Line, Tumor
Colon / metabolism
Colonic Neoplasms / genetics,  metabolism*
Fatty Acids, Volatile / metabolism*
HT29 Cells
Inulin / metabolism
Mice, Inbred C57BL
PPAR gamma / agonists,  genetics,  metabolism*
Transcription, Genetic
Transcriptional Activation
Reg. No./Substance:
0/ANGPTL4 protein, human; 0/Angiopoietins; 0/Fatty Acids, Volatile; 0/PPAR gamma; 9005-80-5/Inulin

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