Takeuchi Asahi, Oda Natsuki, Takada Keigo, Mori Ryosuke, Aida Takumi, Banno Arata, Ebihara Akio, Nagaoka Satoshi
Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
Sci Rep. 2025 Jul 1;15(1):20345. doi: 10.1038/s41598-025-04722-w.
Dietary proteins are absorbed by the intestine as amino acids or peptides. Di- or tripeptides are absorbed via the intestinal peptide transporter 1 (PepT1); however, the intestinal target of oligopeptides larger than tetrapeptides remain unclear, posing a major contradiction in the current protein-peptide nutrition. This study aimed to explore the unidentified function of intestinal alkaline phosphatase (IAP) in regulating cholesterol metabolism using the dietary peptide IIAEK. In IAP-knockout (Akp3) mice, the IIAEK-induced amelioration of cholesterol metabolism via the suppression of intestinal cholesterol absorption was absent. Furthermore, we found that IIAEK specifically interacts with the substrate recognition sites of mouse IAP (Akp3) and human IAP. The IIAEK-human IAP complex interacts with the transmembrane glycoprotein cadherin-17 (CDH17). In conclusion, we demonstrated that IAP is pivotal for the pentapeptide IIAEK-induced amelioration of cholesterol metabolism and serves not only as an enzyme (phosphatase) but also as a glycosylphosphatidylinositol-anchored specific receptor for oligopeptide IIAEK. In addition, we suggest that human cadherin-17 plays a key role in signal transduction in the IIAEK-human IAP complex. Our findings contribute to the understanding of the molecular mechanism of intestinal sensing of oligopeptides (IIAEK) and the development of novel functional foods and medicines targeting IAP to treat lifestyle-related diseases, such as dyslipidaemia.
膳食蛋白质在肠道中以氨基酸或肽的形式被吸收。二肽或三肽通过肠道肽转运体1（PepT1）被吸收；然而，大于四肽的寡肽的肠道靶点仍不清楚，这在当前的蛋白质 - 肽营养领域构成了一个主要矛盾。本研究旨在利用膳食肽IIAEK探索肠道碱性磷酸酶（IAP）在调节胆固醇代谢中的未知功能。在IAP基因敲除（Akp3）小鼠中，IIAEK通过抑制肠道胆固醇吸收诱导的胆固醇代谢改善作用消失。此外，我们发现IIAEK与小鼠IAP（Akp3）和人IAP的底物识别位点特异性相互作用。IIAEK - 人IAP复合物与跨膜糖蛋白钙黏蛋白 - 17（CDH17）相互作用。总之，我们证明了IAP对于五肽IIAEK诱导的胆固醇代谢改善至关重要，并且不仅作为一种酶（磷酸酶），还作为寡肽IIAEK的糖基磷脂酰肌醇锚定特异性受体。此外，我们认为人钙黏蛋白 - 17在IIAEK - 人IAP复合物的信号转导中起关键作用。我们的研究结果有助于理解肠道对寡肽（IIAEK）的感知分子机制，以及开发针对IAP的新型功能性食品和药物来治疗诸如血脂异常等与生活方式相关的疾病。
