title: Bile acid-regulated peroxisome proliferator-activated receptor-α (PPARα) activity underlies circadian expression of intestinal peptide absorption transporter PepT1/Slc15a1.
abstract: Digested proteins are mainly absorbed as small peptides composed of two or three amino acids. The intestinal absorption of small peptides is mediated via only one transport system: the proton-coupled peptide transporter-1 (PepT1) encoded from the soluble carrier protein Slc15a1. In mammals, intestinal expression of PepT1/Slc15a1 oscillates during the daily feeding cycle. Although the oscillation in the intestinal expression of PepT1/Slc15a1 is suggested to be controlled by molecular components of circadian clock, we demonstrated here that bile acids regulated the oscillation of PepT1/Slc15a1 expression through modulating the activity of peroxisome proliferator-activated receptor α (PPARα). Nocturnally active mice mainly consumed their food during the dark phase. PPARα activated the intestinal expression of Slc15a1 mRNA during the light period, and protein levels of PepT1 peaked before the start of the dark phase. After food intake, bile acids accumulated in intestinal epithelial cells. Intestinal accumulated bile acids interfered with recruitment of co-transcriptional activator CREB-binding protein/p300 on the promoter region of Slc15a1 gene, thereby suppressing PPARα-mediated transactivation of Slc15a1. The time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the intestinal expression of PepT1/Slc15a1 during the daily feeding cycle that led to circadian changes in the intestinal absorption of small peptides. These findings suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal peptide transporter.
authors.affiliation: From the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Ayako
authors.initials: A
authors.lastname: Okamura
authors.affiliation: From the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: From the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Adila
authors.initials: A
authors.lastname: Dilxiat
authors.affiliation: From the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kusunose
authors.affiliation: From the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Jia Jun
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: From the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo 162-8480, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Shibata
authors.affiliation: From the Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan and ohdo@phar.kyushu-u.ac.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000378:metabolism; D018938:Caco-2 Cells; D002940:Circadian Rhythm; D003624:Darkness; D004435:Eating; D015870:Gene Expression / Q000528:radiation effects; D006801:Humans; D007408:Intestinal Absorption / Q000235:genetics / Q000528:radiation effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000528:radiation effects; D008027:Light; D057507:Mice, 129 Strain; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D000074011:Peptide Transporter 1; D010455:Peptides / Q000493:pharmacokinetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000235:genetics* / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D047493:PPAR alpha; D000074011:Peptide Transporter 1; D010455:Peptides; C489941:Slc15a1 protein, mouse; D027981:Symporters; D050882:CREB-Binding Protein
keywords: Bile Acid; Circadian Rhythm; Intestinal Epithelium; Peptide Transport; Peroxisome Proliferator-activated Receptor (PPAR)