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

2019 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

消化器内科学

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。