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Pathophysiological mechanism for the high incidence of overeating-induced obesity, NASH and hepatic carcinogenesis in post-menoposal women

Research Project

Project/Area Number 15H04935
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionTokyo Women's Medical University

Principal Investigator

Yamamoto Masakazu  東京女子医科大学, 医学部, 教授 (60220498)

Co-Investigator(Kenkyū-buntansha) 橋本 悦子  東京女子医科大学, 医学部, 教授 (40130273)
有泉 俊一  東京女子医科大学, 医学部, 准教授 (40277158)
徳重 克年  東京女子医科大学, 医学部, 教授 (60188729)
正田 純一  筑波大学, 医学医療系, 教授 (90241827)
柳川 徹  筑波大学, 医学医療系, 准教授 (10312852)
後藤 直宏  東京海洋大学, 食品生産科学科, 教授 (60323854)
磯辺 智範  筑波大学, 医学医療系, 准教授 (70383643)
蕨 栄治  筑波大学, 医学医療系, 講師 (70396612)
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2015: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Keywords脂肪性肝炎 / 肝癌 / 女性ホルモン / 転写因子 / 臓器連環 / 非アルコール性脂肪性肝炎 / 性差 / 遺伝子改変マウス / LPS / 臓器連関 / クッパー細胞 / 非アルコール性脂肪性肝疾患 / エストラジオール / p62遺伝子欠損マウス
Outline of Final Research Achievements

DKO mice represent a phenotype similar to human NASH. This study investigated sex differences in the phenotypes in the mice. Both male and female mice at 8 weeks showed normal liver histology. At 30 weeks, while the livers of male mice became fatty and fibrotic, those of female mice showed only minimal changes of steatosis and no fibrosis. Even for the female mice at 50 weeks, while the large lipid droplets were found, only minimal changes of fatty and fibrotic changes were observed in the livers. The magnitude of NASH histological changes was found to be weaker in female than in male mice. The results importantly suggest that female hormones may attenuate NASH pathophysiology by inhibiting overeating obesity and LPS-induced inflammatory responses.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • Research Products

    (43 results)

All 2018 2017 2016 2015

All Journal Article (17 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 17 results,  Open Access: 9 results,  Acknowledgement Compliant: 1 results) Presentation (17 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Book (9 results)

  • [Journal Article] Deletion of both <i>p62</i> and <i>Nrf2</i> spontaneously results in the development of nonalcoholic steatohepatitis2018

    • Author(s)
      AKIYAMA Kentaro、WARABI Eiji、OKADA Kosuke、YANAGAWA Toru、ISHII Tetsuro、KOSE Katsumi、TOKUSHIGE Katsutoshi、ISHIGE Kazunori、MIZOKAMI Yuji、YAMAGATA Kenji、ONIZAWA Kojiro、ARIIZUMI Shun-ichi、YAMAMOTO Masakazu、SHODA Junichi
    • Journal Title

      Experimental Animals

      Volume: 67 Issue: 2 Pages: 201-218

    • DOI

      10.1538/expanim.17-0112

    • NAID

      130006733609

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.2018

    • Author(s)
      Kawaguchi T, Shima T, Mizuno M, Mitsumoto Y, Umemura A, Kanbara Y, Tanaka S, Sumida Y, Yasui K, Takahashi M, Matsuo K, Itoh Y, Tokushige K, Hashimoto E, Kiyosawa K, Kawaguchi M, Itoh H, Uto H, Komorizono Y, Shirabe K, Takami S, Takamura T, Kawanaka M, Yamada R, Matsuda F, Okanoue T
    • Journal Title

      PLoS One

      Volume: 13

    • NAID

      120006398880

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Skeletal muscle mass to visceral fat area ratio is an important determinant affecting hepatic conditions of non-alcoholic fatty liver disease2017

    • Author(s)
      Shida Takashi、Akiyama Kentaro、Oh Sechang、Sawai Akemi、Isobe Tomonori、Okamoto Yoshikazu、Ishige Kazunori、Mizokami Yuji、Yamagata Kenji、Onizawa Kojiro、Tanaka Hironori、Iijima Hiroko、Shoda Junichi
    • Journal Title

      J Gastroenterol

      Volume: 53 Issue: 4 Pages: 535-547

    • DOI

      10.1007/s00535-017-1377-3

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exercise training enhances in vivo clearance of endotoxin and attenuates inflammatory responses by potentiating Kupffer cell phagocytosis.2017

    • Author(s)
      Komine S, Akiyama K, Warabi E, Oh S, Kuga K, Ishige K, Togashi S, Yanagawa T, Shoda J
    • Journal Title

      Sci Rep

      Volume: 7 Issue: 1 Pages: 11977-11977

    • DOI

      10.1038/s41598-017-12358-8

    • NAID

      120007134775

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Elevated levels of mRNAs encoding dihydropyrimidine dehydrogenase and thymidylate synthase are associated with improved survival of patients with hepatocellular carcinoma treated with S-1.2017

    • Author(s)
      OKANO Y, KURAMOCHI H, NAKAJIMA G, KATAGIRI S, YAMAMOTO M
    • Journal Title

      Oncol lett

      Volume: 14 Issue: 1 Pages: 930-936

    • DOI

      10.3892/ol.2017.6241

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Wisteria floribunda Agglutinin-Sialylated Mucin Core Polypeptide 1 is a Sensitive Biomarker for Biliary Tract Carcinoma and Intrahepatic Cholangiocarcinoma: A Multicenter Study.2016

    • Author(s)
      Shoda J, Matsuda A, Shida T, Yamamoto M, Nagino M, Tsuyuguchi T, Yasaka T, Tazuma S, Uchiyama K, Unno M, Ohkohchi N, Nakanuma Y, Kuno A, Narimatsu H.
    • Journal Title

      J Gastroenterol

      Volume: 52 Issue: 2 Pages: 218-228

    • DOI

      10.1007/s00535-016-1230-0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genomic sequencing identifies ELF3 as a driver of ampullary carcinoma.2016

    • Author(s)
      Yachida Shinichi, Wood Laura D, Suzuki Masami, Takai Erina, Totoki Yasushi, Kato Mamoru, Luchini Claudio, Arai Yasuhito, Nakamura Hiromi, Hama Natsuko, Elzawahry
    • Journal Title

      Cancer Cell

      Volume: 29 Pages: 229-240

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Granulocyte-colony stimulating factor-producing gallbladder carcinoma-include analysis aii case reports:A case report2016

    • Author(s)
      Izumo Wataru, Furukawa Kenji, Katsuragawa Hideo, Tezuka Toru, Furukawa Tatsuya, Hataji Kenichiro, Komatsu Akiko, Shigematsu Kyosuke, Yamamoto Masakazu
    • Journal Title

      Journal of Surgery Case Reports

      Volume: 21 Pages: 87-90

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Application of the clip method, using thread, for duodenal endoscopic mucosal resection2016

    • Author(s)
      Shirai Yuji, Ohki Takeshi, Yamamoto Masakazu
    • Journal Title

      BMJ Case Reprots

      Volume: 10 Pages: 1-4

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Original scientific reports: Clinicopathological findings of remnant pancreatic cancers in survivors following curative resections of pancreatic cancers.2016

    • Author(s)
      Suzuki Shuji, Furukawa Toru, Oshima Nana, Izumo Wataru, Shimizu Kyoko, Yamamoto Masakazu
    • Journal Title

      World Journal of Surgery

      Volume: 40 Pages: 974-981

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ncidence of Esophageal Carcinoma After Surgery for Achalasia: Usefulness of Long Term and Periodic Folloe-Up2016

    • Author(s)
      Ohta Masaho, Narumiya Kosuke, Kudo Kenji, Yagawa Yosuke, Maeda Shinsuke, Osugi Harushi, Yamamoto Msakazu
    • Journal Title

      American Journal of Case Reports

      Volume: 17 Pages: 845-849

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Wisteria floribunda Agglutinin-Sialylated Mucin Core Polypeptide 1 is a Sensitive Biomarker for Biliary Tract Carcinoma and Intrahepatic Cholangiocarcinoma: A Multicenter Study.2016

    • Author(s)
      Shoda J, Matsuda A, Shida T, Yamamoto M, Nagino M, Tsuyuguchi T, Yasaka T, Tazuma S, Uchiyama K, Unno M, Ohkohchi N, Nakanuma Y, Kuno A, Narimatsu H.
    • Journal Title

      J Gastroenterology

      Volume: 52 Pages: 218-228

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Verification of WFA-sialylated MUC1 as a sensitive biliary biomarker for human biliary tract cancer.2016

    • Author(s)
      Yamaguchi T, Yokoyama Y, Ebata T, Matsuda A, Kuno A, Ikehara Y, Narimatsu H, Shoda J, Nagino M.
    • Journal Title

      Anal Sug Oncol

      Volume: 23 Pages: 671-677

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Highly sensitive measurement of qualitative changes in glycosylation of mucin 1 for serodiagnosis of cholangiocarcinoma.2015

    • Author(s)
      Matsuda A, Kuno A, Nakagawa T, Ikegara Y, Irimura T, Yamamoto M, Nakanuma Y, Miyoshi E, Nakamori S, Nakanishi H, Viwatthanasittiphong C, Strivatanakul P, Miwa M, Shoda J, Narimatsu H.
    • Journal Title

      Anal Chem

      Volume: 87 Pages: 7274-81

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Total Volume of Moderate-Vigorous Physical Activity a Week is an Important Factor Improving the Pathophysiology of Obesity-Related Liver Disease.2015

    • Author(s)
      Oh S, Tanaka K, Chiaki K, Tsujimoto T, So R, Shida T, Shoda J
    • Journal Title

      Hepatology

      Volume: 61 Pages: 1205-15

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Whole exome sequencing reveals recurrent mutations in BRCA2 and FAT genes in acinar cell carcinomas of the pancreas.2015

    • Author(s)
      Furukawa T, Sakamoto H, Takeuchi S, Mitra A, Kuboki Y, Yamamoto T, Hatori T, Yamamoto M, Sugiyama M, Ohike N, Yamaguchi H, Shimizu M, Shibata N, Shimizu K, Shiratori K.
    • Journal Title

      Scientific Reports

      Volume: 5 Issue: 1 Pages: 8829-8829

    • DOI

      10.1038/srep08829

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Reverse Trendelenburg position is a safer technique for lowering central venous pressure without decreasing blood pressure than clamping of the inferior vena cava below the liver.2015

    • Author(s)
      Yoneda G, Katagiri S, Yamamoto M.
    • Journal Title

      J Hepatobiliary Pancreat Sci

      Volume: 22 Issue: 6 Pages: 483-6

    • DOI

      10.1002/jhbp.229

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Presentation] Update of Gallstones2017

    • Author(s)
      Junichi Shoda
    • Organizer
      6th A-PHPBA
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] p62:Nrf2遺伝子二重欠損(DKO)♀マウスは♂と比較して非アルコール性脂肪性肝炎(NASH)の肝病変は軽度である2017

    • Author(s)
      長岡亜実 秋山健太郎 蕨栄治 正田純一
    • Organizer
      第21回日本肝臓学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 継続的運動はDHEA産生増加を介して,Kupffer細胞(KC)貪食能の向上によるLPSに対する生体クリアランス増大と炎症応答の低下を誘導する2017

    • Author(s)
      小峰昇一,秋山健太郎,蕨栄治,正田純一
    • Organizer
      第21回日本肝臓学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] NASH自然発症マウスにおける腸内細菌叢と腸管上皮バリア機能の異常2017

    • Author(s)
      秋山健太郎,蕨栄治,正田純一
    • Organizer
      第21回日本肝臓学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 糖尿病関連肝細胞癌の切除成績は良好である2017

    • Author(s)
      有泉俊一, 梁 静, 小寺由人, 大森亜紀子, 山下信吾, 根本 慧, 高橋 豊, 片桐 聡, 江川裕人, 山本雅一
    • Organizer
      第15回日本消化器外科学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 混合型肝癌と細胞肝細胞癌はそれぞれが原発性肝癌である2017

    • Author(s)
      有泉俊一, 小寺由人, 山下信吾, 大森亜紀子, 加藤孝章, 根本 慧, 片桐 聡, 江川裕人, 中野雅行, 山本雅一
    • Organizer
      第22回日本外科病理学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 当院におけるアルコール性及び非アルコール性脂肪性肝疾患に対する肝移植後経過の検討2017

    • Author(s)
      五十嵐悠一, 小木曽智美, 小林睦季, 児玉和久, 谷合麻紀子, 鳥居信之, 橋本悦子, 江川裕人, 山本雅一
    • Organizer
      第103回日本消化器病学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] スポーツ医学より診たNAFLD肥満者における運動療法の有用性2016

    • Author(s)
      呉世昶,志田隆史,正田純一
    • Organizer
      第24回 日本消化器関連学会週間
    • Place of Presentation
      ポートピアホテル(兵庫県神戸市)
    • Year and Date
      2016-11-03
    • Related Report
      2016 Annual Research Report
  • [Presentation] 非アルコール性脂肪性肝疾患に効果的な運動プログラムの検討ー前向きランダム化比較試験よりー2016

    • Author(s)
      蘇リナ,田中 喜代次,正田 純一.
    • Organizer
      第52回日本肝臓学会総会
    • Place of Presentation
      ホテルニューオータニ幕張(千葉県千葉市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] 骨格筋が非アルコール性脂肪性肝疾患(NAFLD)における代謝病態因子に及ぼす影響2016

    • Author(s)
      呉世昶,石原瑞穂,志田隆史,正田純一,
    • Organizer
      第52回日本肝臓学会総会
    • Place of Presentation
      ホテルニューオータニ幕張(千葉県千葉市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] 非アルコール性脂肪性肝炎(NASH)自然発症マウスにおける Kupffer 細胞の表現形質 の変化と発症機序との関連性.2016

    • Author(s)
      秋山健太郎,蕨栄治,正田純一.
    • Organizer
      第102回日本消化器病学会総会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2016-04-21
    • Related Report
      2016 Annual Research Report
  • [Presentation] NAFLDに随伴する中高度肥満と糖尿病がKupffer細胞機能に及ぼす影響と運動療法の効果.2016

    • Author(s)
      志田隆史,秋山健太郎,内田文彦,蘇 リナ,呉 世昶,田中弘教,飯島尋子,正田純一.
    • Organizer
      第102回日本消化器病学会総会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2016-04-21
    • Related Report
      2016 Annual Research Report
  • [Presentation] p62:Nrf2 double knockout mice develop steatohepatitis through the serum endotoxin overload2016

    • Author(s)
      Kentaro Akiyama, Eiji Warabi, Kosuke Okada, Syunnichi Ariizumi, Masakazu Yamamoto, Junnichi Shoda
    • Organizer
      25th Conference of the Asian Pacific Association for the Study of the Liver
    • Place of Presentation
      グランドプリンスホテル新高輪 東京品川
    • Year and Date
      2016-02-23
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The effect of female hormones on NAFLD in p62 knockout mice2016

    • Author(s)
      Miho Ikeuchi, Eiji Warabi, Tsugumi Nagaoka, Syunichi Ariizumi, Masakazu Yamamoto, Junichi Shoda
    • Organizer
      25th Conference of the Asian Pacific Association for the Study of the Liver
    • Place of Presentation
      グランドプリンスホテル新高輪 東京品川
    • Year and Date
      2016-02-23
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 雌性p62遺伝子欠損マウスの表現型の解析-女性ホルモンの過食肥満と肝脂肪化に及ぼす影響の検討2015

    • Author(s)
      池内美穂、蕨栄治、正田純一
    • Organizer
      第19回日本肝臓学会大会
    • Place of Presentation
      グランドプリンスホテル新高輪 東京品川
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] 胆道癌取り扱い規約第6版 遠位胆管癌の評価2015

    • Author(s)
      樋口亮太, 谷澤武久, 山本雅一
    • Organizer
      第51回日本胆道学会学術集会
    • Place of Presentation
      ホテル東日本宇都宮 栃木県宇都宮
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
  • [Presentation] 進行胆嚢癌に対する外科治療-単施設40年の症例における予後因子と切除適応の検討-2015

    • Author(s)
      樋口亮太, 谷澤武久, 植村修一郎, 岡野美々, 矢川陽介, 梶山英樹, 太田岳洋, 新井田達雄, 古川徹, 山本雅一
    • Organizer
      第70回日本消化器外科学会総会
    • Place of Presentation
      アクトシティ浜松 静岡県浜松市
    • Year and Date
      2015-07-15
    • Related Report
      2015 Annual Research Report
  • [Book] 性差による臨床像の差違 ― 胆石症2018

    • Author(s)
      正田純一
    • Publisher
      医学図書出版
    • Related Report
      2017 Annual Research Report
  • [Book] 胆石の形成機序 膵・胆道疾患診療の最前線2018

    • Author(s)
      正田純一
    • Total Pages
      335
    • Publisher
      中山書店
    • Related Report
      2017 Annual Research Report
  • [Book] 消化器外科 起死回生の一手 Ⅱ.下部消化管 直腸癌手術:吻合のトラブルシューティング2017

    • Author(s)
      板橋道朗, 小川真平, 山本雅一
    • Total Pages
      344
    • Publisher
      メジカルビュー社
    • Related Report
      2017 Annual Research Report
  • [Book] 消化器外科 起死回生の一手 Ⅲ.肝・胆・膵/肝切除術 グリソン鞘一括処理時の出血2017

    • Author(s)
      有泉俊一, 山本雅一
    • Total Pages
      344
    • Publisher
      メジカルビュー社
    • Related Report
      2017 Annual Research Report
  • [Book] 肝胆膵2016

    • Author(s)
      川本徹, 山本雅一, 正田純一
    • Publisher
      メディカルビュー社
    • Related Report
      2016 Annual Research Report
  • [Book] 肝胆膵2016

    • Author(s)
      有泉俊一, 山本雅一
    • Publisher
      メディカルビュー社
    • Related Report
      2016 Annual Research Report
  • [Book] 東京女子医科大学総合研究所紀要2016

    • Author(s)
      中島豪, 林和彦, 山本雅一
    • Publisher
      東京女子医科大学
    • Related Report
      2016 Annual Research Report
  • [Book] Horizon of Herbal Medicines2016

    • Author(s)
      Shoda J, Warabi E, Okada K, Yamamoto M
    • Publisher
      Springer
    • Related Report
      2016 Annual Research Report
  • [Book] 肥満と消化器疾患 市民向けガイド2016

    • Author(s)
      正田純一
    • Publisher
      金原出版
    • Related Report
      2016 Annual Research Report

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Published: 2015-04-16   Modified: 2019-03-29  

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