title: Soybean extracts increase cell surface ZIP4 abundance and cellular zinc levels: a potential novel strategy to enhance zinc absorption by ZIP4 targeting.
abstract: Dietary zinc deficiency puts human health at risk, so we explored strategies for enhancing zinc absorption. In the small intestine, the zinc transporter ZIP4 functions as an essential component of zinc absorption. Overexpression of ZIP4 protein increases zinc uptake and thereby cellular zinc levels, suggesting that food components with the ability to increase ZIP4 could potentially enhance zinc absorption via the intestine. In the present study, we used mouse Hepa cells, which regulate mouse Zip4 (mZip4) in a manner indistinguishable from that in intestinal enterocytes, to screen for suitable food components that can increase the abundance of ZIP4. Using this ZIP4-targeting strategy, two such soybean extracts were identified that were specifically able to decrease mZip4 endocytosis in response to zinc. These soybean extracts also effectively increased the abundance of apically localized mZip4 in transfected polarized Caco2 and Madin-Darby canine kidney cells and, moreover, two apically localized mZip4 acrodermatitis enteropathica mutants. Soybean components were purified from one extract and soyasaponin Bb was identified as an active component that increased both mZip4 protein abundance and zinc levels in Hepa cells. Finally, we confirmed that soyasaponin Bb is capable of enhancing cell surface endogenous human ZIP4 in human cells. Our results suggest that ZIP4 targeting may represent a new strategy to improve zinc absorption in humans.
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Department of Bioscience, Fukui Prefectural University, Fukui, Japan.
authors.forename: Katsuma
authors.initials: K
authors.lastname: Ohkura
authors.affiliation: Department of Bioscience, Fukui Prefectural University, Fukui, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Life and Living, Osaka Seikei College, Osaka, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kizu
authors.affiliation: Department of Food Science, Kyoto Women's University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Narita
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan Center for Molecular Imaging Science, RIKEN Kobe Institute, Kobe, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Enomoto
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Miyamae
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Masuda
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nagao
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
authors.affiliation: Department of Bioscience, Fukui Prefectural University, Fukui, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Ohigashi
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, U.S.A.
authors.forename: Glen K
authors.initials: GK
authors.lastname: Andrews
authors.affiliation: Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto, Japan kambe1@kais.kyoto-u.ac.jp.
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003677:Deficiency Diseases / Q000378:metabolism / Q000517:prevention & control; D019587:Dietary Supplements; D004285:Dogs; D004705:Endocytosis; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D005786:Gene Expression Regulation; D006801:Humans; D007408:Intestinal Absorption; D051379:Mice; D010936:Plant Extracts / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012503:Saponins / Q000032:analysis / Q000378:metabolism; D012639:Seeds / Q000737:chemistry; D013025:Glycine max / Q000737:chemistry*; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D005765:Gastrointestinal Agents; D010936:Plant Extracts; D011993:Recombinant Fusion Proteins; D012503:Saponins; C477530:Slc39a4 protein, mouse; C000602851:soyasaponin Bb; D015032:Zinc
keywords: apical membrane; degradation; endocytosis; screening; soyasaponin Bb; zinc transporter