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.
© 2025. The Author(s).