title: Fomiroid A, a novel compound from the mushroom Fomitopsis nigra, inhibits NPC1L1-mediated cholesterol uptake via a mode of action distinct from that of ezetimibe.
abstract: Hypercholesterolemia is one of the key risk factors for coronary heart disease, a major cause of death in developed countries. Suppression of NPC1L1-mediated dietary and biliary cholesterol absorption is predicted to be one of the most effective ways to reduce the risk of hypercholesterolemia. In a screen for natural products that inhibit ezetimibe glucuronide binding to NPC1L1, we found a novel compound, fomiroid A, in extracts of the mushroom Fomitopsis nigra. Fomiroid A is a lanosterone derivative with molecular formula C30H48O3. Fomiroid A inhibited ezetimibe glucuronide binding to NPC1L1, and dose-dependently prevented NPC1L1-mediated cholesterol uptake and formation of esterified cholesterol in NPC1L1-expressing Caco2 cells. Fomiroid A exhibited a pharmacological chaperone activity that corrected trafficking defects of the L1072T/L1168I mutant of NPC1L1. Because ezetimibe does not have such an activity, the binding site and mode of action of fomiroid A are likely to be distinct from those of ezetimibe.
authors.affiliation: FANCL Research Institute, FANCL Corporation, 12-13 Kamishinano, Totsuka-ku, Kanagawa 244-0806, Japan; Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiba
authors.affiliation: FANCL Research Institute, FANCL Corporation, 12-13 Kamishinano, Totsuka-ku, Kanagawa 244-0806, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sakurada
authors.affiliation: FANCL Research Institute, FANCL Corporation, 12-13 Kamishinano, Totsuka-ku, Kanagawa 244-0806, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: FANCL Research Institute, FANCL Corporation, 12-13 Kamishinano, Totsuka-ku, Kanagawa 244-0806, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kioka
authors.affiliation: Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan; Research Institute of Green Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan; Graduate School of Agriculture, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kawagishi
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan; Department of Food and Nutrition, Kyoto Women's University, Kitahiyoshi-cho, Imakumano, Higashiyama-ku, Kyoto 605-8501, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan; Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Kitashirakawa Oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
mesh_terms: D000924:Anticholesteremic Agents / Q000378:metabolism / Q000494:pharmacology*; D001384:Azetidines / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D018938:Caco-2 Cells / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism* / Q000493:pharmacokinetics; D055453:Coriolaceae / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004951:Esterification / Q000187:drug effects; D000069438:Ezetimibe / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D015394:Molecular Structure
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D020719:Glucuronides; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; C511436:ezetimibe glucuronide; C000607159:fomiroid A; D007810:Lanosterol; D002784:Cholesterol; D000069438:Ezetimibe