Physiological significance of brain-derived bile acids as ischemic response factors.

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15009
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48010:Anatomy-related
• Research Institution: Kansai Medical University
• Principal Investigator: OE Souichi 関西医科大学, 医学部, 講師 (70599331)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 脳梗塞 / MCAO / 胆汁酸 / CYP7A1 / RNA安定性 / AUF1

Outline of Final Research Achievements

In this study, we first found that bile acid levels were elevated in the infarcted region using a middle cerebral artery occlusion model in mice. We considered the emergence of bile acids as "brain-derived bile acids" and investigated the synthesis mechanism and physiological function of bile acids in the infarcted region. We found that CYP7A1, the rate-limiting enzyme for bile acid synthesis, is expressed in neurons and is upregulated in the infarct region. We also found that HSD3B7, an enzyme related to bile acid synthesis, is also upregulated, and that AUF1, an RNA-binding protein, is involved in CYP7A1 mRNA stability control. In addition, we generated Cyp7a1 knockout mice, which are deficient in bile acid synthesis, and performed in vivo analyses.

Free Research Field

中枢神経系、脳梗塞、遺伝子発現制御

Academic Significance and Societal Importance of the Research Achievements

脳梗塞は脳血管機能の破綻に起因する代表的な疾患であり、血栓溶解療法や脳保護療法が用いられているがより積極的に脳梗塞病態を改善する方法が求められる。報告者らは脳梗塞モデルマウスにおいて脳梗塞領域のニューロンで「胆汁酸」合成が上昇するという新事実を見出し、新規脳梗塞治療法確立を目指した研究をおこなった。本研究により、神経細胞においてCYP7A1が発現する事、脳梗塞環境下でCYP7A1の発現が上昇する事、RNA結合タンパク質であるAUF1がその発現変化に関わる事等が明らかとなった。これまで着目されていなかった脳での胆汁酸機能の一端を解明した研究結果であり脳梗塞研究のさらなる発展に貢献できると考える。