Cellular cholesterol homeostasis and luminal pH of the Golgi apparatus

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07276
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48010:Anatomy-related
• Research Institution: Juntendo University
• Principal Investigator: Sou Yu-shin 順天堂大学, 医学部, 助教 (60576221)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ゴルジ体 / GPHR / SREBP2 / コレステロール

Outline of Final Research Achievements

Organelles located in the secretory pathway are collectively called acidic organelles, and their lumen is maintained in an acidic condition. To gain insight into the luminal acidic pH of the Golgi apparatus in neuronal cells, we analyzed GPHR knockout mice which can be manipulating the Golgi specific acidic condition. We confirmed that loss of GPHR affects cholesterol biosynthesis via SREBP2 activation in neuronal cells. Morphological analysis provided evidence that GPHR-deficiency course the inhibition neurite outgrowth. These results suggesting that the acidic pH of the Golgi apparatus contributes to cholesterol biosynthesis via activation of SREBP2 in the neuronal cells, and that inhibition lead to suppresses neuronal morphogenesis.

Free Research Field

細胞生物学、組織学

Academic Significance and Societal Importance of the Research Achievements

酸性オルガネラの解析において、ゴルジ体の酸性環境維持機構の生理機能やその破綻による病態生理は、そのほとんどが培養細胞を用いた解析に留まっていた。そこで、本研究課題では、ゴルジ体酸性環境維持に必須な遺伝子GPHRの遺伝子改変動物を用いて、組織レベルにおけるゴルジ体酸性環境維持機構の生理的意義とその破綻に伴うゴルジ体形態異常の病態生理的意義を明らかにした。今後はより詳細な病態発症の分子機構を明らかにすることで、ゴルジ体酸性環境の破綻に起因する病態発症機序の解明および新たな治療法の発見に繋がると期待できる。