Elucidation of the pathological condition of non-alcoholic fatty liver disease regarding retinoid receptor signaling

• Project/Area Number: 16K19336
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: Shirakmai Yohei 岐阜大学, 大学院医学系研究科, 助教 (50632816)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 非アルコール性脂肪性肝炎 / レチノイド / 糖尿病 / 脂肪肝 / NAFLD / 耐糖能 / 肥満 / 内科 / 脂質 / シグナル伝達

Outline of Final Research Achievements

Retinoid receptor signaling is focused to elucidate the pathological condition of non-alcoholic fatty liver disease (NAFLD). Transgenic mice, in which retinoic acid receptor (RAR) or retinoid X receptor (RXR) is dominant-negatively inhibited, were generated and the phenotypes were investigated. Steatohepatitis and glucose intolerance were exacerbated in RXR-transgenic mice fed high-fat diet. The signaling of RXR is thought to play important roles in development and progression of NAFLD and glucose metabolism.

Research Products

• [Journal Article] Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage (2017)
  • Author(s): Ideta, T. Shirakami, Y. Ohnishi, M. Maruta, A. Obara, K. Miyazaki, T. Kochi, T. Sakai, H. Tomita, H. Tanaka, T. Blaner, W. S. Shimizu, M.
  • Journal Title: Oncotarget Volume: 8 Issue: 41 Pages: 70695-70706
  • DOI: 10.18632/oncotarget.19978
  • Peer Reviewed / Open Access
• [Journal Article] Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. (2017)
  • Author(s): Obara K, Shirakami Y, Maruta A, Ideta T, Miyazaki T, Kochi T, Sakai H, Tanaka T, Seishima M, Shimizu M.
  • Journal Title: Oncotarget Volume: 8 Issue: 35 Pages: 58353-58363
  • DOI: 10.18632/oncotarget.16874
  • Peer Reviewed / Open Access
• [Journal Article] Prevention of Colorectal Cancer by Targeting Obesity-Related Disorders and Inflammation (2017)
  • Author(s): Shirakami Yohei、Ohnishi Masaya、Sakai Hiroyasu、Tanaka Takuji、Shimizu Masahito
  • Journal Title: Int J Mol Sci. Volume: 18 Issue: 5 Pages: 908-908
  • DOI: 10.3390/ijms18050908
  • Peer Reviewed / Open Access
• [Journal Article] Preventative Effects of Pentoxifylline on the Development of Colonic Premalignant Lesions in Obese and Diabetic Mice (2017)
  • Author(s): Fukuta K, Shirakami Y, Maruta A, Obara K, Iritani S, Nakamura N, Kochi T, Kubota M, Sakai H, Tanaka T, Shimizu M
  • Journal Title: Int J Mol Sci Volume: 18(2) Issue: 2 Pages: 413-413
  • DOI: 10.3390/ijms18020413
  • Peer Reviewed / Open Access
• [Journal Article] Catechins and Its Role in Chronic Diseases. (2016)
  • Author(s): Shirakami Y, Sakai H, Kochi T, Seishima M, Shimizu M.
  • Journal Title: Adv Exp Med Biol. Volume: 929 Pages: 67-90
  • Peer Reviewed
• [Journal Article] Cimetidine and Clobenpropit Attenuate Inflammation-Associated Colorectal Carcinogenesis in Male ICR Mice (2016)
  • Author(s): Tanaka T, Kochi T, Shirakami Y, Mori T, Kurata A, Watanabe N, Moriwaki H, Shimizu M
  • Journal Title: Cancers Volume: 8 Issue: 2 Pages: 25-25
  • DOI: 10.3390/cancers8020025
  • Peer Reviewed
• [Journal Article] Sodium alginate prevents progression of non-alcoholic steatohepatitis and liver carcinogenesis in obese and diabetic mice. (2016)
  • Author(s): Miyazaki T, Shirakami Y, Kubota M, Ideta T, Kochi T, Sakai H, Tanaka T, Moriwaki H, Shimizu M.
  • Journal Title: Oncotarget. Volume: 7 Pages: 10448-10458
  • Peer Reviewed
• [Journal Article] Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents. (2016)
  • Author(s): Sakai H, Shirakami Y, Shimizu M.
  • Journal Title: World J Gastroenterol Volume: 22(1) Issue: 1 Pages: 394-406
  • DOI: 10.3748/wjg.v22.i1.394
  • Peer Reviewed / Open Access
• [Journal Article] Metabolome Analyses Uncovered a Novel Inhibitory Effect of Acyclic Retinoid on Aberrant Lipogenesis in a Mouse Diethylnitrosamine-Induced Hepatic Tumorigenesis Model. (2016)
  • Author(s): Qin XY, Tatsukawa H, Hitomi K, Shirakami Y, Ishibashi N, Shimizu M, Moriwaki H, Kojima S.
  • Journal Title: Cancer Prev Res Volume: 9 Pages: 205-214
  • Peer Reviewed
• [Presentation] The roles of acyclic retinoid in blocking hepatocellular carcinoma. (2018)
  • Author(s): Shirakami Y
  • Organizer: JSPS拠点形成プログラムシンポジウム「難治疾患に対する分子標的薬創製のための国際共同研究拠点の構築」
• [Presentation] 肥満に関連した肝疾患に対する糖尿病治療薬の作用 (2017)
  • Author(s): 白上洋平、清水雅仁、清島 満
  • Organizer: 第42回日本肝臓学会西部会
• [Presentation] レチノイド受容体遺伝子改変マウスにおける糖・脂質代謝異常 (2017)
  • Author(s): 白上洋平、境 浩康、清水雅仁、清島 満
  • Organizer: 日本レチノイド研究会第28回学術集会
• [Presentation] NASHおよび関連する肝発癌にSGLT-2阻害薬が及ぼす影響 (2017)
  • Author(s): 白上洋平、清水雅仁、清島 満
  • Organizer: JDDW2017（第41回日本肝臓学会大会）
• [Presentation] The sodium glucose cotransporter 2 inhibitor tofogliflozin inhibits obesity-related liver tumorigenesis. (2017)
  • Author(s): 白上洋平、小原功輝、大西雅也、境 浩康、田中卓二、清水雅仁、清島 満
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 糖尿病治療薬SGLT-2阻害薬による肥満関連肝発癌の抑制 (2017)
  • Author(s): 白上洋平、小原功輝、河内隆宏、境 浩康、田中卓二、清水雅仁、清島 満
  • Organizer: 第49回日本臨床分子形態学会総会・学術集会
• [Presentation] 糖尿病治療薬SGLT-2阻害薬が肝脂肪化および肝発癌に及ぼす影響 (2017)
  • Author(s): 白上洋平、小原功輝、境 浩康、田中卓二、清水雅仁、 清島 満
  • Organizer: 第24回肝細胞研究会
• [Presentation] 糖尿病治療薬による肥満に関連する肝発癌の抑制 (2017)
  • Author(s): 白上洋平、小原功輝、境 浩康、田中卓二、清水雅仁、清島 満
  • Organizer: がん予防学術大会2017（第24回日本がん予防学会総会）
• [Presentation] パネルディスカッション「生活習慣病・メタボリックシンドロームからの消化器疾患」 酸化ストレスの制御による肥満関連大腸発癌の抑制 (2017)
  • Author(s): 白上洋平、清水雅仁、清島 満
  • Organizer: 第103回日本消化器病学会総会
• [Presentation] SGLT2阻害薬の脂肪肝および肝発癌に対する効果 (2017)
  • Author(s): 白上洋平、小原功輝、田中卓二、清水雅仁、清島 満
  • Organizer: 第7回肥満と消化器疾患研究会
• [Presentation] Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on liver tumorigenesis in obese mice. (2017)
  • Author(s): Shirakami Y, Obara K, Tanaka T, Shimizu M, Seishima M.
  • Organizer: Asian Pacific Association for the Study of the Liver (APASL) Single Topic Conference
  • Int'l Joint Research
• [Presentation] Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on liver tumorigenesis in obese and diabetic mice. (2017)
  • Author(s): Shirakami Y, Obara K, Ohnishi M, Ideta T, Sakai H, Tanaka T, Shimizu M, Seishima M.
  • Organizer: 108th American Association for Cancer Research (AACR) Annual Meeting
  • Int'l Joint Research
• [Presentation] Preventive effects of pentoxifylline on hepatic tumorigenesis in a novel mouse model of NASH-related liver cancer. (2016)
  • Author(s): Shirakami Y, Sakai H, Ideta T, Takuji Tanaka, Shimizu M, Seishima M.
  • Organizer: 107th American Association for Cancer Research (AACR) Annual Meeting
  • Place of Presentation: New Orleans, USA
  • Int'l Joint Research
• [Presentation] Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid store. (2016)
  • Author(s): Shirakami Y, Ideta T, Sakai H, Tanaka T, Blaner WS, Shimizu M, Seishima M.
  • Organizer: FASEB Science Research Conference (3rd International Conference on Retinoids)
  • Place of Presentation: West Palm Beach, USA
  • Int'l Joint Research
• [Presentation] FXR agonistによる大腸炎および大腸発癌の抑制 (2016)
  • Author(s): 白上洋平, 宮崎恒起, 出田貴康, 境 浩康, 渡部直樹, 田中卓二, 清水雅仁, 清島 満
  • Organizer: 第23回日本がん予防学会総会（がん予防学術大会2016）
  • Place of Presentation: 名古屋
• [Presentation] NASH-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage. (2016)
  • Author(s): Shirakami Y, Ideta T, Sakai H, Tanaka T, Blaner WS, Shimizu M, Seishima M.
  • Organizer: The 12th JSH (Japan Society of Hepatology) Single Topic Conference
  • Place of Presentation: 金沢
• [Presentation] Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage. (2016)
  • Author(s): 白上洋平, 出田貴康, 境 浩康, 田中卓二, 清水雅仁, 清島 満
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 肝レチノイド貯蔵欠如マウスにおいて非アルコール性脂肪肝炎関連肝発癌は抑制される (2016)
  • Author(s): 白上洋平, 出田貴康, 大西雅也, 境 浩康, 田中卓二, 清水雅仁, 清島 満
  • Organizer: 日本レチノイド研究会 第27回学術集会
  • Place of Presentation: 町田
• [Presentation] ワークショップ「消化器疾患と代謝異常の関わり」 糖尿病治療薬を用いた肥満に関連する肝疾患の抑制 (2016)
  • Author(s): 白上洋平, 清水雅仁, 清島 満
  • Organizer: JDDW2016（第58回日本消化器病学会大会）
  • Place of Presentation: 神戸