Induction of intestinal peptide transporter 1 expression during fasting is mediated via peroxisome proliferator-activated receptor alpha.
We previously demonstrated that starvation markedly increased the amount of mRNA and protein levels of the intestinal H+/peptide cotransporter (PEPT1) in rats, leading to altered pharmacokinetics of the PEPT1 substrates. In the present study, the mechanism underlying this augmentation was investigated. We focused on peroxisome proliferator-activated receptor alpha (PPARalpha), which plays a pivotal role in the adaptive response to fasting in the liver and other tissues. In 48-h fasted rats, the expression level of PPARalpha mRNA in the small intestine markedly increased, accompanied by the elevation of serum free fatty acids, which are endogenous PPARalpha ligands. Oral administration of the synthetic PPARalpha ligand WY-14643 to fed rats increased the mRNA level of intestinal PEPT1. Furthermore, treatment of the human intestinal model, Caco-2 cells, with WY-14643 resulted in enhanced PEPT1 mRNA expression and uptake activity of glycylsarcosine. In the small intestine of PPARalpha-null mice, augmentation of PEPT1 mRNA during fasting was completely abolished. In the kidney, fasting did not induce PEPT1 expression in either PPARalpha-null or wild-type mice. Together, these results indicate that PPARalpha plays critical roles in fasting-induced intestinal PEPT1 expression. In addition to the well-established roles of PPARalpha, we propose a novel function of PPARalpha in the small intestine, that is, the regulation of nitrogen absorption through PEPT1 during fasting.
Shimakura
Jin
J
Department of Pharmacy, Kyoto University Hospital, Kyoto 606-8507, Japan.
Terada
Tomohiro
T
Saito
Hirofumi
H
Katsura
Toshiya
T
Inui
Ken-ichi
K
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D018938:Caco-2 Cells; D002478:Cells, Cultured; D005215:Fasting / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism*; D000074011:Peptide Transporter 1; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D008024:Ligands; D047493:PPAR alpha; D000074011:Peptide Transporter 1; D011743:Pyrimidines; D012333:RNA, Messenger; C489940:Slc15a1 protein, rat; D027981:Symporters; C006253:pirinixic acid; D042962:Acyl-CoA Oxidase