Mechanism of amino acid metabolism, alleviation and prevention of hepatic steatosis

• Project/Area Number: 26460998
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagoya University
• Principal Investigator: Takashi Honda 名古屋大学, 医学部附属病院, 助教 (10378052)
• Co-Investigator(Kenkyū-buntansha): 後藤 秀実 名古屋大学, 医学系研究科, 教授 (10215501) ; 石上 雅敏 名古屋大学, 医学部附属病院, 講師 (90378042)
• Co-Investigator(Renkei-kenkyūsha): SHIMOMURA Yoshiharu 名古屋大学, 大学院生命農学研究科, 教授 (30162738)
• Research Collaborator: Feng g. g 愛知医科大学, 薬理学, 講師 (70351111)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 非アルコール性脂肪性肝炎 / 分岐鎖アミノ酸 / 脂肪肝 / コリン欠乏 / 脂質代謝 / 肝癌

Outline of Final Research Achievements

At present, there is no established treatment for nonalcoholic steatohepatitis (NASH). Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis.
In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH.
Serum ALT levels and hepatic TG were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly dcreased in CDHF-BCAA than in CDHF-control. BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels.

Research Products

• [Journal Article] Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice. (2017)
  • Author(s): Honda T, Ishigami M, Luo F, Lingyun M, Ishizu Y, Kuzuya T, Hayashi K, Nakano I, Ishikawa T, Feng GG, Katano Y, Kohama T, Kitaura Y, Shimomura Y, Goto H, Hirooka Y.
  • Journal Title: Metabolism Volume: 69 Pages: 177-187
  • DOI: 10.1016/j.metabol.2016.12.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] DSS colitis promotes tumorigenesis and fibrogenesis in a choline-deficient high-fat diet-induced NASH mouse model. (2016)
  • Author(s): Achiwa K, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Hirooka Y, Katano Y, Goto H.
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 1 Pages: 15-21
  • DOI: 10.1016/j.bbrc.2015.12.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice (2015)
  • Author(s): Luo F, Ishigami M, Achiwa K, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Ishikawa T, Katano Y, Goto H.
  • Journal Title: Dig Dis Sci. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] コリン欠乏高脂肪食によるNASHマウスモデルにおける分岐鎖アミノ酸投与による糖質、アミノ酸代謝の変化 (2016)
  • Author(s): 本多 隆、石上雅敏、安田 諭、伊藤隆徳、野村 彩、加藤幸一郎、新家卓郎、石津洋二、葛谷貞二、林 和彦、廣岡芳樹、後藤秀実
  • Organizer: 第3回肝臓と糖尿病代謝研究会
  • Place of Presentation: 石川県立音楽堂邦楽ホール・交流ホール(石川県金沢市）
• [Presentation] DSS colitis has tumorinogenesis and fibrogenesis in choline-deficiency and high-fat diet induced NASH mouse model (2015)
  • Author(s): Achiwa K, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Hirooka Y, Goto H
  • Organizer: AASLD2015
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2015-11-15
  • Int'l Joint Research
• [Presentation] コリン欠乏高脂肪食によるNASHマウスモデルにおける高血糖を伴わない脂質、分岐鎖アミノ酸代謝の検討 (2015)
  • Author(s): 本多 隆、石上雅敏、安田 諭、川口 彩、加藤幸一郎、新家卓郎、今井則博、阿知波宏一、Luo Fangqiong、山田恵一、石津洋二、葛谷貞二、林 和彦、中野 功、石川哲也、後藤秀実
  • Organizer: 第2回肝臓と糖尿病・代謝研究会
  • Place of Presentation: シーモールパレス（山口県下関市）
  • Year and Date: 2015-05-23
• [Presentation] Oral supplementation of BCAA alleviates hepatic steatosis and liver injury associated with NASH (2014)
  • Author(s): Honda T, Ishigami M, Luo F, Ishizu Y, Kuzuya T, Hayashi K, Shimomura Y, Goto H
  • Organizer: AASLD2014
  • Place of Presentation: Boston (USA)
  • Year and Date: 2014-11-09
• [Presentation] Effects of the Selective Estrogen Receptor Modulator, Raloxifene, on Nonalcoholic Steatohepatitis (2014)
  • Author(s): Luo F, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Goto H
  • Organizer: AASLD2014
  • Place of Presentation: Boston (USA)
  • Year and Date: 2014-11-09
• [Presentation] マウスNASHモデルに対してDSS投与による線維化と発癌モデル作成の試み (2014)
  • Author(s): 阿知波宏一、本多 隆、F.Luo､加藤幸一郎、新家卓郎、今井則博、荒川恭宏、山田恵一、石津洋二、葛谷貞二、林 和彦、石上雅敏、石川哲也、後藤秀実
  • Organizer: 第18回日本肝臓学会大会 (JDDW2014)
  • Place of Presentation: 神戸国際展示場(兵庫県神戸市中央区）
  • Year and Date: 2014-10-23
• [Presentation] コリン欠乏と閉経及びRaloxifeneによるNASH進展への影響 (2014)
  • Author(s): F.Luo､加藤幸一郎、新家卓郎、今井則博、阿知波宏一、荒川恭宏、山田恵一、石津洋二、葛谷貞二、本多 隆、林 和彦、石上雅敏、石川哲也、後藤秀実
  • Organizer: 第18回日本肝臓学会大会 (JDDW2014)
  • Place of Presentation: 神戸国際展示場(兵庫県神戸市中央区）
  • Year and Date: 2014-10-23
• [Presentation] Administration of DSS induced tumorigenesis and fibrosis in NASH mouse model (2014)
  • Author(s): Achiwa K, Ishigami M, Katoh K, Ninoｍi T, Imai N, Luo F, Yamada K, Arakawa T, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Hirooka Y, Goto H
  • Organizer: TAIWAN DIGESTIVE DISEASE WEEK(TDDW)
  • Place of Presentation: Kaohsiung (Taiwan)
  • Year and Date: 2014-10-04
• [Presentation] 卵巣摘出NASHマウスに対するRaloxifeneの効果 (2014)
  • Author(s): Fangqiong LUO､石上雅敏、新家卓郎、今井則博、阿知波宏一、荒川恭宏、山田恵一､中野 聡､石津洋二、葛谷貞二、本多 隆、林 和彦、中野 功、石川哲也、後藤秀実
  • Organizer: 第50回肝臓学会総会
  • Place of Presentation: ホテルニューオータニ(東京都千代田区）
  • Year and Date: 2014-05-30
• [Presentation] 分岐鎖アミノ酸によるNASHマウスモデルにおける肝脂肪抑制効果 (2014)
  • Author(s): 本多 隆、石上雅敏、新家卓郎、今井則博、阿知波宏一、荒川恭宏、山田恵一、中野 聡､石津洋二、葛谷貞二、林 和彦、石川哲也、中野 功、後藤秀実
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2014-04-26