Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine.
Targeted disruption of peptide transporter Pept1 gene in mice significantly reduces dipeptide absorption in intestine.
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DOI：
10.1021/mp8001655
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发表时间：
2008-11
影响因子：
4.9
通讯作者：
Hillgren KM
中科院分区：
文献类型：
--
作者：
Hu Y;Smith DE;Ma K;Jappar D;Thomas W;Hillgren KM
PEPT1是一种高容量、低亲和力的多肽转运体，介导肠道和肾脏对二肽和三肽的摄取。PEPT1还具有运输治疗药物的能力以及作为抗炎治疗靶点的潜力。为了进一步了解特定的多肽转运体在肠道生理学、药理学和病理生理学中的相关性，我们通过靶向基因破坏产生了Pept1基因缺失的小鼠。Pept1基因在内源Pept1启动子的控制下插入LacZ报告基因而被干扰。然后对野生型和Pept1基因缺失的小鼠进行表型分析，以及甘氨酰肌氨酸(GlySar)的体外肠道摄取、原位肠道灌流和体内药代动力学研究。Pept1基因缺失的小鼠在肠道和肾脏中缺乏PEPT1蛋白的表达，而这种多肽转运蛋白通常在这些组织中表达。Pept1基因缺陷的小鼠被发现是存活的、有生育能力的、长到正常大小和体重的，并且没有任何明显的异常。然而，Pept1缺失显著降低了模型二肽GlySar的肠道摄取和有效渗透性(即至少减少了80%)，以及它在灌胃后的口服吸收(即大约50%)。相比之下，静脉注射GlySar后，野生型和Pept1缺失型动物之间的血浆GlySar谱几乎是重叠的。这些新的发现提供了强有力的证据，证明PEPT1在体内口服吸收二肽方面具有重要作用。
PEPT1 is a high-capacity, low-affinity peptide transporter that mediates the uptake of di- and tripeptides in the intestine and kidney. PEPT1 also has significance in its ability to transport therapeutic agents and because of its potential as a target for anti-inflammatory therapies. To further understand the relevance of specific peptide transporters in intestinal physiology, pharmacology and pathophysiology, we have generated Pept1 null mice by targeted gene disruption. The Pept1 gene was disrupted by insertion of a lacZ reporter gene under the control of the endogenous Pept1 promoter. Phenotypic profiling of wild-type and Pept1 null mice was then performed, along with in vitro intestinal uptake, in situ intestinal perfusion and in vivo pharmacokinetic studies of glycylsarcosine (GlySar). Pept1 null mice lacked expression of PEPT1 protein in the intestine and kidney, tissues in which this peptide transporter is normally expressed. Pept1-deficient mice were found to be viable, fertile, grew to normal size and weight, and were without any obvious abnormalities. Nevertheless, Pept1 deletion dramatically reduced the intestinal uptake and effective permeability of the model dipeptide GlySar (i.e., by at least 80%), and its oral absorption following gastric gavage (i.e., by about 50%). In contrast, the plasma profiles of GlySar were almost superimposable between wild-type and Pept1 null animals after intravenous dosing. These novel findings provide strong evidence that PEPT1 has a major role in the in vivo oral absorption of dipeptides.
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影响因子：
4.8
作者：
RONG, LA;FEI, YJ;LEIBACH, FH
通讯作者：
LEIBACH, FH
影响因子：
3.7
作者：
Adachi, Y;Suzuki, H;Sugiyama, Y
通讯作者：
Sugiyama, Y
影响因子：
4.7
作者：
Hu, Yongjun;Shen, Hong;Smith, David E.
通讯作者：
Smith, David E.
影响因子：
3.7
作者：
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通讯作者：
AMIDON, GL
影响因子：
64.8
作者：
FEI, YJ;KANAI, Y;HEDIGER, MA
通讯作者：
HEDIGER, MA