Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 304, Issue 11, Pages G1025-G1037Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00293.2012
Keywords
short-chain fatty acids; peroxisome proliferator-activated receptor-gamma; fasting-induced adipose factor; angiopoietin-like protein 4; Clostridium tyrobutyricum
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Funding
- European Community's Seventh Framework Programme [215553-2 (Cross-Talk), 222720-2 (TORNADO), HEALTH-F4-2007-201052 (MetaHIT)]
- French National Research Agency (ANR) project MicroObes
- Swedish Research Council
- European Marie-Curie Initial Training Network Cross-Talk [215553]
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Short-chain fatty acids (SCFAs), such as butyrate and propionate, are metabolic products of carbohydrate fermentation by the microbiota and constitute the main source of energy for host colonocytes. SCFAs are also important for gastrointestinal health, immunity, and host metabolism. Intestinally produced angiopoietin-like protein 4 (ANGPTL4) is a secreted protein with metabolism-altering properties and may offer a route by which microbiota can regulate host metabolism. Peroxisome proliferator-activated receptor (PPAR)-gamma has previously been shown to be involved in microbiota-induced expression of intestinal ANGPTL4, but the role of bacterial metabolites in this process has remained elusive. Here, we show that the SCFA butyrate regulates intestinal ANGPTL4 expression in a PPAR-gamma-independent manner. Although PPAR-gamma is not required for butyrate-driven intestinal ANGPTL4 expression, costimulating with PPAR-gamma ligands and SCFAs leads to additive increases in ANGPTL4 levels. We suggest that PPAR-gamma and butyrate rely on two separate regulatory sites, a PPAR-responsive element downstream the transcription start site and a butyrate-responsive element(s) within the promoter region, 0.5 kb upstream of the transcription start site. Furthermore, butyrate gavage and colonization with Clostridium tyrobutyricum, a SCFA producer, can independently induce expression of intestinal ANGPTL4 in germ-free mice. Thus, oral administration of SCFA or use of SCFA-producing bacteria may be additional routes to maintain intestinal ANGPTL4 levels for preventive nutrition or therapeutic purposes.
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