title: ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways.
abstract: 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)-γ 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-γ-independent manner. Although PPAR-γ is not required for butyrate-driven intestinal ANGPTL4 expression, costimulating with PPAR-γ ligands and SCFAs leads to additive increases in ANGPTL4 levels. We suggest that PPAR-γ 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.
authors.affiliation: Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology (MTC), Stockholm, Sweden.
authors.forename: Agata
authors.initials: A
authors.lastname: Korecka
authors.forename: Tomas
authors.initials: T
authors.lastname: de Wouters
authors.forename: Antonietta
authors.initials: A
authors.lastname: Cultrone
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lapaque
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.forename: Joël
authors.initials: J
authors.lastname: Doré
authors.forename: Hervé M
authors.initials: HM
authors.lastname: Blottière
authors.forename: Velmurugesan
authors.initials: V
authors.lastname: Arulampalam
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D018938:Caco-2 Cells; D048014:Clostridium tyrobutyricum; D020895:Enterocytes / Q000378:metabolism; D005856:Germ-Free Life; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology; D054892:Metagenome; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D020218:Response Elements; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D002087:Butyrates; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Clostridium tyrobutyricum; angiopoietin-like protein 4; fasting-induced adipose factor; peroxisome proliferator-activated receptor-γ; short-chain fatty acids