Investigation of a novel mechanism of NASH pathogenesis focused on bile acid metabolism, and exploration of a new therapeutic strategy

• Project/Area Number: 17K15929
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: OKUSHIN KAZUYA 東京大学, 医学部附属病院, 助教 (40753918)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 非アルコール性脂肪性肝疾患 / 非アルコール性脂肪肝炎 / 胆汁酸代謝 / 脂質代謝 / bile salt export pump / ノックアウトマウス / siRNA / BSEP / コレステロール代謝 / LDLR / 発現制御 / 内科 / 臨床

Outline of Final Research Achievements

We previously reported that the intrahepatic expression of the bile salt export pump (BSEP) was downregulated during progression of NAFLD, suggesting that BSEP is involved in the pathogenesis of NASH. In this study, to investigate the role of BSEP in the pathogenesis of NASH, we have designed two approaches to regulate BSEP in mouse models via genetic modification: in vivo gene knockdown and gene knockout.
Knockdown of BSEP gene in wild type mice induced the enhanced expression of the cholesterol uptake pathway, including low-density lipoprotein receptor. BSEP heterozygous knockout mice fed a high-fat diet exhibited significant alterations of the expression levels of genes related to bile acid and lipid metabolism in the liver and ileum, resulting in alleviated steatosis and less weight gain. These results suggest the importance of BSEP for maintenance of bile acid and cholesterol metabolism. Further investigations of the functions of BSEP will provide insight into NASH pathogenesis.

Academic Significance and Societal Importance of the Research Achievements

NAFLD/NASHの病態と胆汁酸代謝の関連は注目度が高く、国内外で積極的に研究が行われている。実際に、オベチコール酸を筆頭に胆汁酸代謝を標的とした各種薬剤が基礎的および臨床的な検討が加えられた上で、最も進んだものでPhaseⅢまで進行している。
そのような中、我々は多数例のヒト肝組織での胆汁酸代謝関連遺伝子発現の変化をいち早く報告してきた。本研究はこれらヒト肝組織での変化から得られた仮説を、マウスモデルにおいて検証することを起点としており、胆汁酸トランスポーターBSEPが肝臓から腸管にわたる代謝に重要な役割を果たすことを明らかとした極めてオリジナリティが高い研究と考えられる。

Research Products

• [Journal Article] Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients (2020)
  • Author(s): Enooku K, Tsutsumi T, Kondo M, Fujiwara N, Sasako T, Shibahara J, Kado A, Okushin K, Fujinaga H, Nakagomi R, Minami T, Sato M, Uchino K, Nakagawa H, Kondo Y, Asaoka Y, Tateishi R, Ueki K, Ikeda H, Yoshida H, Moriya K, Yotsuyanagi H, Kadowaki T, Koike K
  • Journal Title: J Gastroenterol Volume: 55 Issue: 2 Pages: 227-243
  • DOI: 10.1007/s00535-019-01633-2
  • Peer Reviewed / Open Access
• [Journal Article] Noninvasive diagnostic criteria for nonalcoholic steatohepatitis based on gene expression levels in peripheral blood mononuclear cells. (2019)
  • Author(s): Akira Kado,Takeya Tsutsumi,Kenichiro Enooku,Hidetaka Fujinaga,Kazuhiko Ikeuchi,Kazuya Okushin,Kyoji Moriya,Hiroshi Yotsuyanagi,Kazuhiko Koike
  • Journal Title: Journal of gastroenterology Volume: 54 Issue: 8 Pages: 730-741
  • DOI: 10.1007/s00535-019-01565-x
  • Peer Reviewed
• [Presentation] 胆汁酸トランスポーターBSEPのヘテロノックアウトは高脂肪食摂取マウスの肝脂肪化に対して抑制的作用を有する (2020)
  • Author(s): 奥新和也、堤武也、小池和彦
  • Organizer: 第106回消化器病学会総会
• [Presentation] disruption of the homeostasis in lipid metabolism by knock-down of bile salt export pump may be involved in NASH pathogenesis in mouse model (2017)
  • Author(s): Kazuya Okushin, Takeya Tsutsumi, Kenichiro Enooku, Hidetaka Fujinaga, Akira Kado, Kyoji Moriya, Hiroshi Yotsuyanagi, and Kazuhiko Koike
  • Organizer: American Association for the Study of Liver Diseases (AASLD) 2017
  • Int'l Joint Research