Production and phenotype analysis of mouse models with humanized bile acid composition

• Project/Area Number: 17H04167
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical University
• Principal Investigator: Honda Akira 東京医科大学, 医学部, 教授 (10468639)
• Co-Investigator(Kenkyū-buntansha): 岩本 淳一 東京医科大学, 医学部, 准教授 (10384950) ; 池上 正 東京医科大学, 医学部, 教授 (40439740) ; 宮崎 照雄 東京医科大学, 医学部, 講師 (60532687)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
• Keywords: 胆汁酸 / ノックアウトマウス / Cyp2c70 / Cyp2a12 / 消化器病学 / 胆汁酸代謝

Outline of Final Research Achievements

The bile acid (BA) composition in mice is substantially different from that in humans. We generated Cyp2a12-/-(2a12KO), Cyp2c70-/-(2c70KO) and Cyp2c70-/-Cyp2a12-/-(DKO) mice using the CRISPR-Cas9 system to study the regulations of BA metabolism under humanized BA composition. 2a12KO mice showed the accumulation of deoxycholic acids (DCAs), whereas 2c70KO mice lacked muricholic acids (MCAs) and exhibited markedly increased hepatobiliary proportions of chenodeoxycholic acid (CDCA). In DKO mice, not only DCAs or CDCAs but DCAs, CDCAs and lithocholic acids (LCAs) were all elevated. The BA pool was markedly reduced in 2c70KO and DKO mice, but the farnesoid X receptor (FXR) was not activated. It was suggested that the cytokine/c-Jun N-terminal kinase signaling pathway and the pregnane X receptor-mediated pathway are the predominant mechanisms, preferred over the FXR/SHP and FXR/FGF15 pathways, for controlling BA synthesis under hydrophobic BA composition.

Academic Significance and Societal Importance of the Research Achievements

消化器系疾患の病態モデルをマウスで作成するにあたり、マウスとヒトの胆汁酸組成の違いによって、ヒトの病態との決定的な種差を生じる可能性が指摘されている。本研究で開発したヒト型の胆汁酸組成を有するマウスは、今後多くの消化器疾患モデルの作成に利用可能であると考えられ、病態の解明のみならず治療法の開発においても有用なツールになることが予想される。

Research Products

• [Journal Article] Regulations of bile acid metabolism in mouse models with hydrophobic bile acid composition. (2020)
  • Author(s): Honda A, Miyazaki T, Iwamoto J, Hirayama T, Morishita Y, Monma T, Ueda H, Mizuno S, Sugiyama F, Takahashi S, Ikegami T.
  • Journal Title: Journal of Lipid Research Volume: 61 Issue: 1 Pages: 54-69
  • DOI: 10.1194/jlr.ra119000395
  • Peer Reviewed
• [Journal Article] Impaired bile acid metabolism with defectives of mitochondrial-tRNA taurine modification and bile acid taurine conjugation in the taurine depleted cats (2020)
  • Author(s): Miyazaki Teruo、Sasaki Sei-Ich、Toyoda Atsushi、Wei Fan-Yan、Shirai Mutsumi、Morishita Yukio、Ikegami Tadashi、Tomizawa Kazuhito、Honda Akira
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 4915-4915
  • DOI: 10.1038/s41598-020-61821-6
  • Peer Reviewed / Open Access
• [Journal Article] Human-specific dual regulations of FXR-activation for reduction of fatty liver using <i>in vitro</i> cell culture model (2019)
  • Author(s): Miyazaki T, Honda A, Ikegami T, Iida T, Matsuzaki Y
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 64 Issue: 2 Pages: 112-123
  • DOI: 10.3164/jcbn.18-80
  • NAID: 130007606956
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Presentation] Roles of bile acids in hepatobiliary diseases: a novel approach using mouse models with humanized bile acid composition (2019)
  • Author(s): Honda A, Miyazaki T, Ikegami T
  • Organizer: 日本消化器関連学会週間2019
• [Presentation] ヒト型胆汁酸マウスにおける胆汁酸代謝 (2019)
  • Author(s): 本多 彰，宮崎照雄，岩本淳一，平山 剛，池上 正
  • Organizer: 第41回胆汁酸研究会