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Genetic and environmental factors related to onset and severity of CTLN2 in citrin deficiency

Research Project

Project/Area Number 15K09595
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionKagoshima University

Principal Investigator

Saheki Takeyori  鹿児島大学, 医歯学総合研究科, 客員研究員 (10056070)

Co-Investigator(Kenkyū-buntansha) 井ノ上 逸朗  国立遺伝学研究所, 総合遺伝研究系, 教授 (00192500)
矢崎 正英  信州大学, 学術研究院保健学系, 教授 (70372513)
森山 光章  大阪府立大学, 生命環境科学研究科, 准教授 (20275283)
Research Collaborator FUNAHASHI Aki  鹿児島大学, 医歯学総合研究科
KURODA Eishi  鹿児島大学, 医歯学総合研究科
YASUDA Izumi  鹿児島大学, 医歯学総合研究科
SETOGAWA Yoshiko  鹿児島大学, 医歯学総合研究科
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordscitrin deficiency / CTLN2 / hyperammonemia / sugar toxicity / NADH / ornithine / aspartate / alanine / シトリン欠損症モデルマウス / 高アンモニア血症 / 糖質の毒性 / アミノ酸の効果 / ショ糖摂取 / 忌避 / アミノ酸 / 滅菌餌 / 修飾遺伝子 / 尿素サイクル酵素 / 成長障害
Outline of Final Research Achievements

Aversion against sugars is the remarkable characteristics of citrin deficiency. We showed that two factors simultaneously induced by sugar intake, an increased cytosolic NADH and decreased ATP in the liver, send signals to the brain, to avoid intake of excess sugars.
On the other hand, we have shown that intake of protein and some amino acids ameliorate sugar toxicity. In this research, we clarified that a severe hyperammonemia induced in the model mice was greatly relieved by oral administration of ornithine + aspartate or alanine. Although aspartate can’t directly enter the hepatocyte carrying urea cycle, it can be converted into alanine in the small intestine, which then can enter the hepatocyte with urea cycle and converted back to aspartate, resulting in almost complete dissolution of hyperammonemia.

Report

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

    (23 results)

All 2017 2016 2015

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 3 results,  Acknowledgement Compliant: 1 results) Presentation (16 results) (of which Int'l Joint Research: 8 results,  Invited: 8 results) Book (2 results)

  • [Journal Article] Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency.2017

    • Author(s)
      Saheki T, Inoue K, Ono H, Fujimoto Y, Furuie S, Yamamura KI, Kuroda E, Ushikai M, Asakawa A, Inui A, Eto K, Kadowaki T, Moriyama M, Sinasac DS, Yamamoto T, Furukawa T, Kobayashi K.
    • Journal Title

      Molecular Genetics and Metabolism

      Volume: 120 Issue: 4 Pages: 306-316

    • DOI

      10.1016/j.ymgme.2017.02.004

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency.2017

    • Author(s)
      Saheki T, Inoue K, Ono H, Fujimoto Y, Furuie S, Yamamura KI, Kuroda E, Ushikai M, Asakawa A, Inui A, Eto K, Kadowaki T, Moriyama M, Sinasac DS, Yamamoto T, Furukawa T, Kobayashi K.
    • Journal Title

      Mol Genet Metab.

      Volume: 120 Pages: 306-316

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Circulating tricarboxylic acid cycle metabolite levels in citrin-deficient children with metabolic adaptation, with and without sodium pyruvate treatment.2017

    • Author(s)
      Nagasaka H, Komatsu H, Inui A, Nakacho M, Morioka I, Tsukahara H, Kaji S, Hirayama S, Miida T, Kondou H, Ihara H, Yagi M, Kizaki Z, Bessho K, Kodama T, Iijima K, Saheki T, Yorifuji T, Honda A
    • Journal Title

      Mol. Genet. Metab.

      Volume: 120 Issue: 3 Pages: 207-212

    • DOI

      10.1016/j.ymgme.2016.12.011

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic hepatitis without hepatic steatosis caused by citrin deficiency in a child.2017

    • Author(s)
      Inui A, Hashimoto T, Sogo T, Komatsu H, Saheki T, Fujisawa T.
    • Journal Title

      Hepatol Res.

      Volume: 46 Issue: 4 Pages: 357-362

    • DOI

      10.1111/hepr.12559

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mechanism for increased hepatic glycerol synthesis in the citrin/mitochondria glycerol-3-phosphate dehydrogenase double-knockout mouse: Urine glycerol and glycerol 3-phosphate as potential diagnostic markers of human citrin deficiency.2015

    • Author(s)
      Moriyama M, Fujimoto Y, Rikimaru S,Ushikai M, Kuroda E, Kawabe K, Takano K,Asakawa A, Inui A, Eto K, Kadowaki T, Sinasac DS, Okano Y, Yazaki M, Ikeda SI,Zhang C, Song YZ,Sakamoto O, Kure S, Mitsubuchi H, Endo F, Horiuchi M, Nakamura Y, Yamamura KI, Saheki T.
    • Journal Title

      Biochim Biophys Acta.

      Volume: 印刷中 Issue: 9 Pages: 1787-1795

    • DOI

      10.1016/j.bbadis.2015.04.023

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] An Overview of Citrin Deficiency: A newly established inborn error of metabolism: Pathogenesis, pathophysiology and treatment, Seminar on Citrin Deficiency2017

    • Author(s)
      Saheki, T.
    • Organizer
      Seminar on Citrin Deficiency
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] How to manage Citrin Deficincy -for the patients and their families-2017

    • Author(s)
      Saheki, T.
    • Organizer
      Seminar on Citrin Deficiency
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] To find out Patients with Adult-onset Type II Citrullinemia (CTLN2): Pathogenesis, Pathophysiology, Diagnosis and Treatment -Patients dislike carbohydrate and sweets, and can’t drink alcohol.-2017

    • Author(s)
      Saheki, T.
    • Organizer
      遺伝性肝疾患学会
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Pathogenesis, Pathophysiology and Treatment of Citrin Deficiency, -Treatment of Hyperammonemia in Citrin Deficiency with Amino Acids by using the Model, Citrin/mGPD double-KO, Mice-2017

    • Author(s)
      Saheki T, Kuroda E, Funahashi A, Yasuda I, Setogawa Y, Gao GH, Ushikai M, Horiuchi M, Moriyama M
    • Organizer
      International Congress on Inborn Error of Metabolism (ICIEM) 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Study on Treatment of Citrin Deficiency by using the Animal Model: Effects of Amino acids2017

    • Author(s)
      Saheki T, Kuroda E, Funahashi A, Yasuda I, Setogawa Y, Gao GH, Ushikai M, Horiuchi M, Moriyama M
    • Organizer
      International Symposium on Precision Medicine and Genetics
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] シトリン欠損症に関わって―科学における運命的出会い―2017

    • Author(s)
      佐伯武賴
    • Organizer
      日本先天代謝異常学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] モデルマウスを用いるシトリン欠損症の研究(1)高アンモニア血症マウスの作成2017

    • Author(s)
      佐伯武頼、黒田英志、舟橋亞希、安田いづみ、瀬戸川芳子、高青華、古川龍彦、堀内正久、森山光章
    • Organizer
      日本先天代謝異常学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] モデルマウスを用いるシトリン欠損症の研究(2)高い治療効果を持つアミノ酸の探索2017

    • Author(s)
      佐伯武頼、黒田英志、舟橋亞希、安田いづみ、瀬戸川芳子、高青華、古川龍彦、堀内正久、森山光章
    • Organizer
      日本先天代謝異常学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] モデルマウスを用いるシトリン欠損症に有効なアミノ酸の探索2016

    • Author(s)
      佐伯武賴、安田いづみ、黒田英志、瀬戸川芳子、森山光章、山村研一、古川龍彦
    • Organizer
      第58回日本先天代謝異常学会;第14回アジア先天代謝異常症シンポジウム
    • Place of Presentation
      京王プラザホテル(東京都・新宿区)
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] 滅菌処理した食餌(CE-2)によるシトリン欠損症モデルマウス症状の重症化2016

    • Author(s)
      佐伯武賴、黒田英志、安田いづみ、 瀬戸川芳子、古川龍彦、森山光章
    • Organizer
      第58回日本先天代謝異常学会;第14回アジア先天代謝異常症シンポジウム
    • Place of Presentation
      京王プラザホテル(東京都・新宿区)
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report
  • [Presentation] Treatment of Citrin Deficiency: Effect of amino acids on increases in hepatic cytosolic NADH or glycerol 3-phosphate induced by sucrose or ethanol in citrin deficiency model mice2016

    • Author(s)
      Takeyori Saheki, Izumi Yasuda, Tatsuhiko Furukawa, Yuki Fujimoto, Sumie Furuie, Ken-ichi Yamamura
    • Organizer
      Asia Europe Workshop on Inborn Error of Metabolism
    • Place of Presentation
      Seoul, Korea
    • Year and Date
      2016-03-30
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] シトリン欠損症におけるアミノ酸の治療効果の解析2016

    • Author(s)
      佐伯武賴、藤本侑希、古家澄江、 山村研一、安田いづみ、森山光章、 古川龍彦
    • Organizer
      日本病態栄養学会
    • Place of Presentation
      パシフィコ横浜、神奈川県、横浜市
    • Year and Date
      2016-01-08
    • Related Report
      2015 Research-status Report
  • [Presentation] Current State and Treatment of Citrin Deficiency2016

    • Author(s)
      Takeyori Saheki
    • Organizer
      Basis and Application of Precision Medicine at Quanzhou
    • Place of Presentation
      Quanzhou (China)
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] An Overview of Citrin Deficiency2016

    • Author(s)
      Takeyori Saheki
    • Organizer
      Sympsium on Citrin deficiency at Guangzhou
    • Place of Presentation
      Guangzhou (China)
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] シトリン欠損症モデルマウスにおけるグルコースの毒性2015

    • Author(s)
      佐伯武頼、藤本侑希、古家澄江、山村研一、森山光章、古川龍彦
    • Organizer
      日本先天代謝異常学会
    • Place of Presentation
      大阪府立国際会議場、大阪府、大阪市
    • Year and Date
      2015-11-12
    • Related Report
      2015 Research-status Report
  • [Presentation] 成人発症II型シトルリン血症(CTLN2)における発症誘導因子の作用機構解明を目指して2015

    • Author(s)
      佐伯武賴、古家澄江、藤本侑希、山村研一
    • Organizer
      ビタミンB研究委員会
    • Place of Presentation
      東大寺ミュージアム、奈良県、奈良市
    • Year and Date
      2015-06-04
    • Related Report
      2015 Research-status Report
  • [Book] シトリン欠損症2017

    • Author(s)
      佐伯武賴
    • Total Pages
      128
    • Publisher
      諷詠社
    • ISBN
      9784434229794
    • Related Report
      2017 Annual Research Report
  • [Book] シトリン欠損症―医者も知らない特異な疾患ー2017

    • Author(s)
      佐伯武賴
    • Total Pages
      128
    • Publisher
      風詠社
    • Related Report
      2016 Research-status Report

URL: 

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

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