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

• Project/Area Number: 15K09595
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kagoshima 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: ¥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)
• Keywords: citrin 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.

Research Products

• [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
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Presentation] An Overview of Citrin Deficiency: A newly established inborn error of metabolism: Pathogenesis, pathophysiology and treatment, Seminar on Citrin Deficiency (2017)
  • Author(s): Saheki, T.
  • Organizer: Seminar on Citrin Deficiency
  • 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
  • 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
  • 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
  • Int'l Joint Research / Invited
• [Presentation] Study on Treatment of Citrin Deficiency by using the Animal Model: Effects of Amino acids (2017)
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [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 mice (2016)
  • 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
  • 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
• [Presentation] Current State and Treatment of Citrin Deficiency (2016)
  • Author(s): Takeyori Saheki
  • Organizer: Basis and Application of Precision Medicine at Quanzhou
  • Place of Presentation: Quanzhou (China)
  • Int'l Joint Research / Invited
• [Presentation] An Overview of Citrin Deficiency (2016)
  • Author(s): Takeyori Saheki
  • Organizer: Sympsium on Citrin deficiency at Guangzhou
  • Place of Presentation: Guangzhou (China)
  • 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
• [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
• [Book] シトリン欠損症 (2017)
  • Author(s): 佐伯武賴
  • Total Pages: 128
  • Publisher: 諷詠社
  • ISBN: 9784434229794
• [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