Cargando…
IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1
IIAEK (Ile-Ile-Ala-Glu-Lys, lactostatin) is a novel cholesterol-lowering pentapeptide derived from bovine milk β-lactoglobulin. However, the molecular mechanisms underlying the IIAEK-mediated suppression of intestinal cholesterol absorption are unknown. Therefore, we evaluated the effects of IIAEK o...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551322/ https://www.ncbi.nlm.nih.gov/pubmed/32961978 http://dx.doi.org/10.3390/nu12092859 |
_version_ | 1783593157908234240 |
---|---|
author | Takeuchi, Asahi Hisamatsu, Kentaro Okumura, Natsuki Sugimitsu, Yuki Yanase, Emiko Ueno, Yoshihito Nagaoka, Satoshi |
author_facet | Takeuchi, Asahi Hisamatsu, Kentaro Okumura, Natsuki Sugimitsu, Yuki Yanase, Emiko Ueno, Yoshihito Nagaoka, Satoshi |
author_sort | Takeuchi, Asahi |
collection | PubMed |
description | IIAEK (Ile-Ile-Ala-Glu-Lys, lactostatin) is a novel cholesterol-lowering pentapeptide derived from bovine milk β-lactoglobulin. However, the molecular mechanisms underlying the IIAEK-mediated suppression of intestinal cholesterol absorption are unknown. Therefore, we evaluated the effects of IIAEK on intestinal cholesterol metabolism in a human intestinal model using Caco-2 cells. We found that IIAEK significantly reduced the expression of intestinal cholesterol metabolism-associated genes, particularly that of the ATP-binding cassette transporter A1 (ABCA1). Subsequently, we chemically synthesized a novel molecular probe, IIXEK, which can visualize a complex of target proteins interacting with photoaffinity-labeled IIAEK by fluorescent substances. Through photoaffinity labeling and MS analysis with IIXEK for the rat small intestinal mucosa and intestinal lipid raft fractions of Caco-2 cells, we identified intestinal alkaline phosphatase (IAP) as a specific molecule interacting with IIAEK and discovered the common IIAEK-binding amino acid sequence, GFYLFVEGGR. IIAEK significantly increased IAP mRNA and protein levels while decreasing ABCA1 mRNA and protein levels in Caco-2 cells. In conclusion, we found that IIAEK targets IAP to improve cholesterol metabolism via a novel signaling pathway involving the specific activation of IAP and downregulation of intestinal ABCA1. |
format | Online Article Text |
id | pubmed-7551322 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75513222020-10-16 IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1 Takeuchi, Asahi Hisamatsu, Kentaro Okumura, Natsuki Sugimitsu, Yuki Yanase, Emiko Ueno, Yoshihito Nagaoka, Satoshi Nutrients Article IIAEK (Ile-Ile-Ala-Glu-Lys, lactostatin) is a novel cholesterol-lowering pentapeptide derived from bovine milk β-lactoglobulin. However, the molecular mechanisms underlying the IIAEK-mediated suppression of intestinal cholesterol absorption are unknown. Therefore, we evaluated the effects of IIAEK on intestinal cholesterol metabolism in a human intestinal model using Caco-2 cells. We found that IIAEK significantly reduced the expression of intestinal cholesterol metabolism-associated genes, particularly that of the ATP-binding cassette transporter A1 (ABCA1). Subsequently, we chemically synthesized a novel molecular probe, IIXEK, which can visualize a complex of target proteins interacting with photoaffinity-labeled IIAEK by fluorescent substances. Through photoaffinity labeling and MS analysis with IIXEK for the rat small intestinal mucosa and intestinal lipid raft fractions of Caco-2 cells, we identified intestinal alkaline phosphatase (IAP) as a specific molecule interacting with IIAEK and discovered the common IIAEK-binding amino acid sequence, GFYLFVEGGR. IIAEK significantly increased IAP mRNA and protein levels while decreasing ABCA1 mRNA and protein levels in Caco-2 cells. In conclusion, we found that IIAEK targets IAP to improve cholesterol metabolism via a novel signaling pathway involving the specific activation of IAP and downregulation of intestinal ABCA1. MDPI 2020-09-18 /pmc/articles/PMC7551322/ /pubmed/32961978 http://dx.doi.org/10.3390/nu12092859 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Takeuchi, Asahi Hisamatsu, Kentaro Okumura, Natsuki Sugimitsu, Yuki Yanase, Emiko Ueno, Yoshihito Nagaoka, Satoshi IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1 |
title | IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1 |
title_full | IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1 |
title_fullStr | IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1 |
title_full_unstemmed | IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1 |
title_short | IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1 |
title_sort | iiaek targets intestinal alkaline phosphatase (iap) to improve cholesterol metabolism with a specific activation of iap and downregulation of abca1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551322/ https://www.ncbi.nlm.nih.gov/pubmed/32961978 http://dx.doi.org/10.3390/nu12092859 |
work_keys_str_mv | AT takeuchiasahi iiaektargetsintestinalalkalinephosphataseiaptoimprovecholesterolmetabolismwithaspecificactivationofiapanddownregulationofabca1 AT hisamatsukentaro iiaektargetsintestinalalkalinephosphataseiaptoimprovecholesterolmetabolismwithaspecificactivationofiapanddownregulationofabca1 AT okumuranatsuki iiaektargetsintestinalalkalinephosphataseiaptoimprovecholesterolmetabolismwithaspecificactivationofiapanddownregulationofabca1 AT sugimitsuyuki iiaektargetsintestinalalkalinephosphataseiaptoimprovecholesterolmetabolismwithaspecificactivationofiapanddownregulationofabca1 AT yanaseemiko iiaektargetsintestinalalkalinephosphataseiaptoimprovecholesterolmetabolismwithaspecificactivationofiapanddownregulationofabca1 AT uenoyoshihito iiaektargetsintestinalalkalinephosphataseiaptoimprovecholesterolmetabolismwithaspecificactivationofiapanddownregulationofabca1 AT nagaokasatoshi iiaektargetsintestinalalkalinephosphataseiaptoimprovecholesterolmetabolismwithaspecificactivationofiapanddownregulationofabca1 |