Development of a new therapeutic treatment for metabolic diseases based on the solution of the relationship between bile acids and homeostasis of lipids and sugars

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390006
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Tohoku University
• Principal Investigator: MANO Nariyasu 東北大学, 病院, 教授 (50323035)
• Co-Investigator(Kenkyū-buntansha): SHIMADA Miki 東北大学, 病院, 准教授 (10196488)
• Project Period (FY): 2009 – 2011
• Keywords: 分析化学 / メタボロミクス / 抱合型胆汁酸 / プロテオミクス / 翻訳後修飾 / 質量分析 / 胆汁酸結合タンパク質

Research Abstract

We analyzed proteome in cultured cells after bile acid stimulation, and found quantitative variation for posttranslational modifications of α-enolase and peroxiredoxin-1. By cleavable affinity gel extraction, we found intracellular carrier proteins and some enzymes for bile acid metabolism besides peroxiredoxin-1 as bile acid binding proteins in hepatocytes. We developed a method for one 18O-atom labeling at C-terminal of tryptic digested peptides, which allowed application to quantitative proteomics. The method for comprehensive analysis of bile acid conjugates developed in this study was useful for finding specific metabolites in some diseases.

Research Products

• [Journal Article] Screening of antibiotics that interact with organic anion-transporting polypeptides 1B1 and 1B3 using fluorescent probes (2011)
  • Author(s): Hiroaki Yamaguchi, Toshiko Takeuchi, Masahiro Okada, Minako Kobayashi, Michiaki Unno, Takaaki Abe, Junichi Goto, Takanori Hishinuma, Miki Shimada, and Nariyasu Mano
  • Journal Title: Biol. Pharm. Bull Volume: 34 Pages: 389-395
  • Peer Reviewed
• [Journal Article] Identification and elimination of ion suppression in the quantitative analysis of sirolimus in human blood by LC/ESI-MS/MS (2011)
  • Author(s): Nariyasu Mano, Marina Nozawa, Mayumi Sato, Masaru Mori, Hiroaki Yamaguchi, Katsuhiro Kanda, Makoto Nogami, Junichi Goto, and Miki Shimada
  • Journal Title: J. Chromatogr. B Volume: 879 Pages: 968-974
  • Peer Reviewed
• [Journal Article] An accurate quantitative LC/ESI-MS/MS method for sirolimus in human whole blood (2011)
  • Author(s): Nariyasu Mano, Mayumi Sato, Marina Nozawa, Yotaro Matsumoto, Masaru Mori, Hiroaki Yamaguchi, Junichi Goto, and Miki Shimada
  • Journal Title: J. Chromatogr. B Volume: 879 Pages: 987-992
  • Peer Reviewed
• [Journal Article] Biliary bile acids in birds of the Cotingidae family : Taurine-conjugated (24R, 25R)-3α, 7α, 24-trihydroxy-5β-cholestan-27-oic acid and two epimers (25R and 25S)of 3α, 7α-dihydroxy-5β-cholestan-27-oic acid (2011)
  • Author(s): Lee R. Hagey, Takashi Iida, Shoujiro Ogawa, Yuuki Adachi, Mizuho Une, Kumiko Mushiake, Masamitsu Maekawa, Miki Shimada, Nariyasu Mano, and Alan F. Hofmann
  • Journal Title: Steroids Volume: 76 Pages: 1126-1135
  • Peer Reviewed
• [Journal Article] Chemical synthesis of (22E)-3α, 6α, 7α, 12α-tetrahydroxy-5β-chol-22-en-24-oic acid and its N-acylamidated conjugates with glycine or taurine : Precursors of the [22, 23-3H] labelled tracers (2011)
  • Author(s): Shoujiro Ogawa, Yuuki Adachi, Genta Kakiyama, Miki Shimada, Nariyasu Mano, Junichi Goto, and Takashi Iida
  • Journal Title: Chem. Pharm. Bull Volume: 58 Pages: 1103-1106
  • Peer Reviewed
• [Journal Article] LC-MS/MS coupled with immunoaffinity extraction for determination of estrone, 17β-estradiol and estrone 3-sulfate in human plasma (2010)
  • Author(s): Jun Hosogi, Hideyuki Tanaka, Kazuhiro Fujita, Takashi Kuwabara, Shigeo Ikegawa, Norihiro Kobayashi, Nariyasu Mano, and Junichi Goto
  • Journal Title: J. Chromatogr. B Volume: 878 Pages: 222-227
  • Peer Reviewed
• [Journal Article] Chemical synthesis of 3-and 21-monosulfates and their double-conjugates of tetrahydrocorticosteroids in the 5α-and 5β-series (2010)
  • Author(s): Rika Okihara, Kuniko Mitamura, Maki Hasegawa, Megumi Mori, Akina Muto, Genta Kakiyama, Shoujiro Ogawa, Takashi Iida, Miki Shimada, Nariyasu Mano, and Shigeo Ikegawa : Potential corticoid metabolites
  • Journal Title: Chem. Pharm. Bull Volume: 58 Pages: 344-353
  • Peer Reviewed
• [Journal Article] Gene expression profiling defines the role of ATP-exposed keratinocytes in skin inflammation (2010)
  • Author(s): Hiroshi Ohara, Rumiko Saito, Satoshi Hirakawa, Miki Shimada, Nariyasu Mano, Ryuhei Okuyama, and Setsuya Aiba
  • Journal Title: J. Dermatol. Sci Volume: 58 Pages: 143-151
  • Peer Reviewed
• [Journal Article] Transport of estrone 3-sulfate mediated by organic anion transporter OATP4C1 : Estrone 3-sulfate binds to the different recognition site for digoxin in OATP4C1 (2010)
  • Author(s): Hiroaki Yamaguchi, Misa Sugie, Masahiro Okada, Tsuyoshi Mikkaichi, Takafumi Toyohara, Takaaki Abe, Junichi Goto, Takanori Hishinuma, Miki Shimada, and Nariyasu Mano
  • Journal Title: Drug Metabol. Pharmacokinet Volume: 25 Pages: 314-317
  • Peer Reviewed
• [Journal Article] Production of 18O-single labeled peptide fragments during trypsin digestion of proteins for quantitative proteomics using nanoLC-ESI-MS/MS (2010)
  • Author(s): Masaru Mori, Kohei Abe, Hiroaki Yamaguchi, Junichi Goto, Miki Shimada, and Nariyasu Mano
  • Journal Title: J. Proteome Res Volume: 9 Pages: 3741-3749
  • Peer Reviewed
• [Journal Article] A new, major C27 biliary bile acid in the red-winged tinamou (Rhynchotus rufescens):(25R)-1β, 3α, 7α-trihydroxy-5β-cholestan-27-oic acid (2009)
  • Author(s): Lee R. Hagey, Genta Kakiyama, Akina Muto, Takashi Iida, Kumiko Mushiake, Takaaki Goto, Nariyasu Mano, Junichi Goto, Cleida A. Oliveria, and Alan F. Hofmann
  • Journal Title: J. Lipid Res Volume: 50 Pages: 651-657
  • Peer Reviewed
• [Journal Article] Chemical synthesis of 3β-sulfooxy-7β-hydroxy-24-nor-5-cholenoic acid : an internal standard for mass spectrometric analysis of the abnormal Δ5-bile acids occurring in Niemann-Pick disease (2009)
  • Author(s): Genta Kakiyama, Akina Muto, Miki Shimada, Nariyasu Mano, Junichi Goto, Alan F. Hofmann, and Takashi Iida
  • Journal Title: Steroids Volume: 74 Pages: 766-772
  • Peer Reviewed
• [Journal Article] Analysis of phosphorylated peptides by double pseudo-neutral loss extraction coupled with derivatization using N-(4-bromobenzoyl)aminoethanethiol (2009)
  • Author(s): Nariyasu Mano, Sayaka Aoki, Takuma Yamazaki, Yoko Nagaya, Masaru Mori, Kohei Abe, Miki Shimada, Hiroaki Yamaguchi, Takaaki Goto, and Junichi Goto
  • Journal Title: Anal. Chem Volume: 81 Pages: 9395-9401
  • Peer Reviewed
• [Journal Article] DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells
  • Author(s): Yuriko Saiki, Yuki Yoshino, Hiroko Fujimura, Tatsuya Manabe, Yuki Kudo, Miki Shimada, Nariyasu Mano, Tomohiro Nakano, Yoonha Lee, Shinjiro Shimizu, Shinya Oba, Sho Fujiwara, Hideyuki Shimizu, Na Chen, Zhaleh K Nezhad, Guo Jin, Shinichi Fukushige, Makoto Sunamura, Masaharu Ishida, Fuyuhiko Motoi, Shinichi Egawa, Michiaki Unno, and Akira Horii
  • Journal Title: Biochem. Biophys. Res. Commun., in press
  • Peer Reviewed
• [Presentation] 膵がんゲムシタビン療法のPK/PGx (2012)
  • Author(s): 鈴木裕之、工藤由起、相馬真志、菊地正史、木皿重樹、松浦正樹、久道周彦、江川新一、海野倫明、島田美樹、眞野成康
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌
  • Year and Date: 20120329-31
• [Presentation] タンデム質量分析法を活用した抱合型胆汁酸メタボローム解析法の構築 (2011)
  • Author(s): 前川正充、森大、鈴木裕之、大野耕策、入戸野博、小川祥二郎、柿山玄太、飯田隆、後藤順一、島田美樹、眞野成康
  • Organizer: 第24回バイオメディカル分析科学シンポジウム
  • Place of Presentation: 大山
  • Year and Date: 20110831-0902
• [Presentation] LC/ESI-MS/MS method for focusing metabolome of bile acid conjugates (2011)
  • Author(s): Masamitsu Maekawa, Masaru Mori, Hiroyuki Suzuki, Takashi Iida, Miki Shimada, and Nariyasu Mano
  • Organizer: 59th ASMS Conference
  • Place of Presentation: Denver, USA(Poster)
  • Year and Date: 20110605-0609
• [Presentation] LC/ESI-MS/MS method for therapeutic drug monitoring of sirolimus in human whole blood (2011)
  • Author(s): Nariyasu Mano, Mayumi Sato, and Miki Shimada
  • Organizer: IUPAC International Congress on Analytical Sciences 2011 (ICAS 2011)
  • Place of Presentation: 京都
  • Year and Date: 20110522-0526
• [Presentation] 培養細胞中のソラフェニブおよび代謝物定量法の構築 (2011)
  • Author(s): 大川星美、鈴木裕之、森大、前川正充、島田美樹、眞野成康
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 20110328-0331
• [Presentation] HPLCによるゲムシタビンおよび代謝物の血中濃度測定法の構築 (2011)
  • Author(s): 工藤由起、田村淳、前川正充、鈴木裕之、森大、島田美樹、眞野成康
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 20110328-0331
• [Presentation] LC/ESI-MS/MSによる抱合型胆汁酸のメタボローム解析法の検討 (2011)
  • Author(s): 前川正充、森大、鈴木裕之、坂本修、大浦敏博、虻川大樹、大野耕策、入戸野博、飯田隆、島田美樹、眞野成康
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
  • Year and Date: 20110328-0331
• [Presentation] 血中シロリムスのLC/ESI-MS/MS分析におけるマトリクス効果の排除 (2010)
  • Author(s): 佐藤真由美、野澤真里奈、森大、山口浩明、神田勝弘、野上真、後藤順一、島田美樹、眞野成康
  • Organizer: 第21回クロマトグラフィー科学会議
  • Place of Presentation: 西宮
  • Year and Date: 20101021-1023
• [Presentation] Analysis of chenodeoxycholate-binding proteins in rat brain and pituitary by mass spectrometry coupled with cleavable affinity extraction (2010)
  • Author(s): Nariyasu Mano, Kohei Abe, Masaru Mori, Koichi Sato, Hiroaki Yamaguchi, Miki Shimada, Takaaki Goto, and Junichi Goto
  • Organizer: XXI International Bile Acid Meeting ; Bile Acids as Metabolic Integrators and Therapeutics
  • Place of Presentation: Freiburg, Germany(Poster)
  • Year and Date: 20101007-1008
• [Presentation] Determination of multi-conjugated bile acids in the urine of patients with Niemann-Pick disease, type C by liquid chromatography/electrospray ionization tandem mass spectrometry (2010)
  • Author(s): Masamitsu Maekawa, Yasushi Misawa, Ayako Sotoura, Osamu Sakamoto, Toshihiro Ohura, Daiki Abukawa, Takehiko Inoue, Kousaku Ohno, Akina Muto, Hajime Takei, Hiroshi Nittono, Shoujiro Ogawa, Genta Kakiyama, Takashi Iida, Alan F. Hofmann, Junichi Goto, Miki Shimada, and Nariyasu Mano
  • Organizer: XXI International Bile Acid Meeting ; Bile Acids as Metabolic Integrators and Therapeutics
  • Place of Presentation: Freiburg, Germany(Poster)
  • Year and Date: 20101007-1008
• [Presentation] LC/ESI-MS/MSを用いたNiemann-Pick病C型患者尿中の多重抱合型胆汁酸測定法 (2010)
  • Author(s): 前川正充、三澤靖、外浦亜耶子、坂本修、大浦敏博、虻川大樹、井上岳彦、大野耕策、武藤晃奈、武井一、入戸野博、小川祥二郎、柿山玄太、飯田隆、Alan. F. Hofmann、後藤順一、島田美樹、眞野成康
  • Organizer: 第23回バイオメディカル分析科学シンポジウム
  • Place of Presentation: 松島
  • Year and Date: 20100721-0723
• [Presentation] プロテオーム変動解析を目的としたトリプシン酵素反応を活用する18O一置換標識法の性能評価 (2010)
  • Author(s): 森大、島田美樹、眞野成康
  • Organizer: 第23回バイオメディカル分析科学シンポジウム
  • Place of Presentation: 松島
  • Year and Date: 20100721-0723
• [Presentation] LC/ESI-MS/MSによるNiemann-Pick病C型患者尿中多重抱合型胆汁酸の高感度分析 (2010)
  • Author(s): 前川正充、三澤靖、外浦亜耶子、坂本修、大浦敏博、虻川大樹、井上岳彦、大野耕策、武藤晃奈、武井一、入戸野博、小川祥二郎、柿山玄太、飯田隆、Alan F. Hofmann、後藤順一、島田美樹、眞野成康
  • Organizer: 第17回クロマトグラフィーシンポジウム
  • Place of Presentation: 広島
  • Year and Date: 20100603-0605
• [Presentation] Double pseudo-neutral loss extraction coupled with specific derivatization for analysis of phosphoproteins (2010)
  • Author(s): Nariyasu Mano, Takuma Yamazaki, Sayaka Aoki, Masaru Mori, Takaaki Goto, and Miki Shimada
  • Organizer: 58th ASMS Conference
  • Place of Presentation: Salt Lake City(Poster)
  • Year and Date: 20100523-0527
• [Presentation] Quantitative performance of a novel trypsin-catalyzed 18O-single labeling method for serum proteomics (2010)
  • Author(s): Masaru Mori, Miki Shimada, Nariyasu Mano
  • Organizer: 58th ASMS Conference
  • Place of Presentation: Salt Lake City, USA(Poster)
  • Year and Date: 20100523-0527
• [Presentation] 18O一置換標識法とnanoLC/ESI-MS/MSによる血清プロテオーム解析法の有用性 (2010)
  • Author(s): 森大、島田美樹、眞野成康
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 20100328-0330
• [Presentation] 疾患マーカー探索を目指した抱合型胆汁酸のメタボローム解析手法の検討 (2010)
  • Author(s): 前川正充、森大、鈴木裕之、島田美樹、眞野成康
  • Organizer: 第32回胆汁酸研究会
  • Place of Presentation: 仙台
  • Year and Date: 2010-11-06
• [Presentation] LC/ESI-MS/MSによるNiemann-Pick病C型患者尿中異常胆汁酸の高感度分析 (2010)
  • Author(s): 三澤靖、外浦亜耶子、後藤順一、島田美樹、眞野成康、前川正充、坂本修、大浦敏博、虻川大樹、井上岳彦、大野耕策、武藤晃奈、武井一、入戸野博、小川祥二郎、柿山玄太、飯田隆、Alan F. Hofmann
  • Organizer: 第6回東日本胆汁酸研究会
  • Place of Presentation: 東京
  • Year and Date: 2010-07-31
• [Presentation] LC/MS/MSを用いる血中シロリムス濃度測定法の改良 (2009)
  • Author(s): 野澤真里奈、島田美樹、山口浩明、後藤順一、眞野成康
  • Organizer: 第49回日本臨床化学会年次学術集会
  • Place of Presentation: 長崎
  • Year and Date: 20090918-0920
• [Presentation] プロテオーム変動解析を目的としたトリプシンを用いる18O一置換法 (2009)
  • Author(s): 森大、阿部幸平、山口浩明、後藤順一、島田美樹、眞野成康
  • Organizer: 第34回日本医用マススペクトル学会
  • Place of Presentation: 大阪
  • Year and Date: 20090910-0911
• [Presentation] 新規アフィニティー抽出法を用いたラット肝組織中ケノデオキシコール酸結合タンパク質の解析 (2009)
  • Author(s): 三澤靖、佐藤光市、森大、阿部幸平、山口浩明、後藤順一、島田美樹、眞野成康
  • Organizer: 第34回日本医用マススペクトル学会
  • Place of Presentation: 大阪
  • Year and Date: 20090910-0911
• [Presentation] 18O一置換標識法によるプロテオームの量的変動解析に関する検討 (2009)
  • Author(s): 森大、阿部幸平、山口浩明、後藤順一、島田美樹、眞野成康
  • Organizer: 第22回バイオメディカル分析科学シンポジウム
  • Place of Presentation: 各務原
  • Year and Date: 20090715-0717
• [Presentation] LC/ESI-MS/MSによる三重抱合型異常胆汁酸の高感度定量法の構築 (2009)
  • Author(s): 三澤靖、外浦亜耶子、阿部幸平、山口浩明、柿山玄太、飯田隆、後藤順一、島田美樹、眞野成康
  • Organizer: 第22回バイオメディカル分析科学シンポジウム
  • Place of Presentation: 各務原
  • Year and Date: 20090715-0717
• [Book] Capter 10.Analysis of Bile Acids inSteroid Analysis Second Edition (2010)
  • Author(s): Jan Sjovall, William J. Griffiths, Kenneth D. R. Setchell, Nariyasu Mano, and Junichi Goto
  • Total Pages: 837-966
  • Publisher: Springer
• [Book] 薬学分析科学の最前線, 第7章質量分析法の展開, 質量分析法による生体内分子の高感度分析と挙動解析 (2009)
  • Author(s): 眞野成康
  • Total Pages: 118-119
  • Publisher: じほう
• [Remarks]
  • URL: http://www.pharm.hosp.tohoku.ac.jp/Study/gyouseki.html