Induction of intestinal peptide transporter 1 expression during fasting is mediated via peroxisome proliferator-activated receptor α
Induction of intestinal peptide transporter 1 expression during fasting is mediated via peroxisome proliferator-activated receptor α
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DOI：
10.1152/ajpgi.00171.2006
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发表时间：
2006-11-01
影响因子：
4.5
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
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作者：
Shimakura, Jin;Terada, Tomohiro;Inui, Ken-ichi
我们以前证明，饥饿显着增加大鼠肠道H+/肽协同转运蛋白（PEPT 1）的mRNA和蛋白质水平的量，导致改变PEPT 1底物的药代动力学。在本研究中，这种增强的机制进行了调查。我们专注于过氧化物酶体增殖物激活受体α（PPAR α），它在肝脏和其他组织对禁食的适应性反应中起着关键作用。在禁食48 h的大鼠中，小肠中的PPAR α mRNA表达水平显著增加，伴随着血清游离脂肪酸的升高，这是内源性PPAR α配体。经口给予喂食大鼠合成的PPAR α配体WY-14643可增加肠道PEPT 1的mRNA水平。此外，用WY-14643处理人肠模型Caco-2细胞导致增强的PEPT 1 mRNA表达和甘氨酰肌氨酸摄取活性。在PPARalpha缺失小鼠的小肠中，禁食期间PEPT 1 mRNA的增加完全消失。在肾脏中，禁食不会诱导PPARalpha-null或野生型小鼠中的PEPT 1表达。总之，这些结果表明，PPAR α在禁食诱导的肠道PEPT 1表达中起着关键作用。除了PPARalpha的既定作用外，我们还提出了PPARalpha在小肠中的一种新功能，即在禁食期间通过PEPT 1调节氮吸收。
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 (PPAR alpha), 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 PPAR alpha mRNA in the small intestine markedly increased, accompanied by the elevation of serum free fatty acids, which are endogenous PPAR alpha ligands. Oral administration of the synthetic PPAR alpha 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 PPAR alpha-null mice, augmentation of PEPT1 mRNA during fasting was completely abolished. In the kidney, fasting did not induce PEPT1 expression in either PPAR alpha-null or wild-type mice. Together, these results indicate that PPAR alpha plays critical roles in fasting-induced intestinal PEPT1 expression. In addition to the well-established roles of PPAR alpha, we propose a novel function of PPAR alpha in the small intestine, that is, the regulation of nitrogen absorption through PEPT1 during fasting.