Gastrointestinal stability and DPP-IV inhibitory activity of tilapia (Oreochromis niloticus) viscera hydrolysate-derived novel peptides LPCL and TPFLPDE, with LPCL-modulated GLP-1 and PepT1 expression in STC-1 cells

  • Food Res Int. 2025 Nov:219:116986. doi: 10.1016/j.foodres.2025.116986.
Rhessa Grace Guanga Ortizo  1 ,  Ching-Shu Lai  2 ,  Choirul Anwar  2 ,  Vishal Sharma  3 ,  Pei-Pei Sun  2 ,  Chiu-Wen Chen  4 ,  Cheng-Di Dong  5 ,  Mei-Ling Tsai  6
Affiliations
  • 1. Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan; College of Fisheries and Aquatic Sciences, Iloilo State University of Fisheries Science and Technology, Barotac Nuevo, Iloilo 5007, Philippines; Institute of Aquatic Science and Technology, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan.
  • 2. Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan.
  • 3. Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan; Institute of Aquatic Science and Technology, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan.
  • 4. Institute of Aquatic Science and Technology, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan; Department of Marine Environmental Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan.
  • 5. Institute of Aquatic Science and Technology, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan; Department of Marine Environmental Engineering, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan. Electronic address: [email protected].
  • 6. Department of Seafood Science, National Kaohsiung University of Science and Technology, Kaohsiung 811, Taiwan. Electronic address: [email protected].
PMID: 40922149 DOI: 10.1016/j.foodres.2025.116986
Abstract

Dipeptidyl-peptidase (DPP)-IV inhibition by penultimate N-terminus Pro-containing peptides is a promising strategy for Type 2 diabetes (T2D) management, as it prevents the degradation of incretin Hormones (DPP-IV substrates) like glucagon-like peptide-1 (GLP-1), thereby prolonging their half-life. However, the stability and bio-accessibility of these peptides are crucial to their efficacy in orally administered therapeutics. We previously identified LPCL and TPFLPDE peptides from tilapia viscera by-products hydrolysates, which exhibited significant DPP-IV inhibition in vitro and in situ while effectively preserving active GLP-1 levels after 2 h treatment in STC-1 cells under basal glucose conditions. In this study, we assessed the gastrointestinal (GI) stability of these peptides using a static in vitro GI digestion model and evaluated their DPP-IV inhibition capacity after post-GI digestion and post-DPP-IV pre-incubation. Our findings revealed that both peptides retained their DPP-IV inhibition capacity after GI digestion, with RP-HPLC and mass spectrometry confirming their intact forms. At post-DPP-IV pre-incubation, peptides exhibited decreased DPP-IV inhibition potency, indicating a substrate-type inhibition mechanism, forming N-terminal dipeptide fragments. Furthermore, we extended our previous findings by demonstrating that LPCL not only inhibits DPP-IV activity but also modulates GLP-1 expression and increases PepT1 protein levels in STC-1 cells. Unlike glycyl sarcosine, a known PepT1 substrate, LPCL effectively activates the PepT1 extracellular domain (ECD), leading to increased receptor expression and receptor-ligand interactions, as confirmed by molecular docking analysis. These results provide novel insights into the functional roles of LPCL in modulating DPP-IV activity and GLP-1 expression, potentially via PepT1 ECD conformational stabilization.

Keywords
DPP-IV inhibition; Functional food; GI stability; GLP-1; Molecular docking; PepT1 extracellular domain; Substrate-type inhibitors.
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