title: A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1.
abstract: Monocarboxylate transporter isoform-1 (MCT1) plays an important role in the absorption of short-chain fatty acids (SCFAs) in the colon. Butyrate, a major SCFA, serves as the primary energy source for the colonic mucosa, maintains epithelial integrity, and ameliorates intestinal inflammation. Previous studies have shown substrate (butyrate)-induced upregulation of MCT1 expression and function via transcriptional mechanisms. The present studies provide evidence that short-term MCT1 regulation by substrates could be mediated via a novel nutrient sensing mechanism. Short-term regulation of MCT1 by butyrate was examined in vitro in human intestinal C2BBe1 and rat intestinal IEC-6 cells and ex vivo in rat intestinal mucosa. Effects of pectin feeding on MCT1, in vivo, were determined in rat model. Butyrate treatment (30-120 min) of C2BBe1 cells increased MCT1 function {p-(chloromercuri) benzene sulfonate (PCMBS)-sensitive [(14)C]butyrate uptake} in a pertussis toxin-sensitive manner. The effects were associated with decreased intracellular cAMP levels, increased V(max) of butyrate uptake, and GPR109A-dependent increase in apical membrane MCT1 level. Nicotinic acid, an agonist for the SCFA receptor GPR109A, also increased MCT1 function and decreased intracellular cAMP. Pectin feeding increased apical membrane MCT1 levels and nicotinate-induced transepithelial butyrate flux in rat colon. Our data provide strong evidence for substrate-induced enhancement of MCT1 surface expression and function via a novel nutrient sensing mechanism involving GPR109A as a SCFA sensor.
authors.affiliation: Section of Digestive Diseases & Nutrition, Dept. of Medicine, Univ. of Illinois at Chicago, Chicago, IL 60612, USA. alipb@uic.edu
authors.forename: Alip
authors.initials: A
authors.lastname: Borthakur
authors.forename: Shubha
authors.initials: S
authors.lastname: Priyamvada
authors.forename: Anoop
authors.initials: A
authors.lastname: Kumar
authors.forename: Arivarasu A
authors.initials: AA
authors.lastname: Natarajan
authors.forename: Ravinder K
authors.initials: RK
authors.lastname: Gill
authors.forename: Waddah A
authors.initials: WA
authors.lastname: Alrefai
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dudeja
mesh_terms: D000818:Animals; D002087:Butyrates / Q000378:metabolism / Q000494:pharmacology*; D018938:Caco-2 Cells; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000378:metabolism; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009525:Niacin / Q000494:pharmacology; D010368:Pectins / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D002087:Butyrates; D005576:Colforsin; D000242:Cyclic AMP; D027501:Monocarboxylic Acid Transporters; D009525:Niacin; D010368:Pectins; D037342:Pertussis Toxin; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C554445:Hcar2 protein, rat