The molecular mechanism of purinergic chemical transmission in the development of Non-alcoholic steatohepatitis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17988
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kyushu University
• Principal Investigator: Sakamoto Shohei 九州大学, 大学病院, 特別教員 (90761502)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: Purinergic signaling / VNUT / NASH

Outline of Final Research Achievements

ATP is accumulated and stored within the secretory vesicles by Vesicular Nucleotide Transporter（VNUT） and is released by several stimulation. Exocytotic release of ATP leads to purinergic chemical transmission. The purpose of this research was to clarify the role and the molecular mechanism of purinergic chemical transmission in the development of Non-alcoholic steatohepatitis（NASH）. We revealed that glucose and apoptosis stimulate ATP secretion from the hepatocytes and macrophages. Released ATP induces and sustains the inflammation through purinergic chemical transmission and these reactions are depending on the function of VNUT. These results suggest that purinergic chemical transmission might promote the development of NASH and VNUT could be a new therapeutic target for NASH.

Free Research Field

内分泌代謝学

Academic Significance and Societal Importance of the Research Achievements

本研究において、肝細胞およびマクロファージのVNUTを介したプリン作動性化学伝達がマクロファージを介した炎症を活性化することを見出し、VNUTがNASH発症に促進的に働いていることが推察された。VNUTを介したプリン作動性化学伝達によるNASH発症メカニズムの解明は有効な治療法の乏しいNASHの新たな治療薬開発へ繋がることが期待される。また、申請者はクロドロン酸が細胞レベルだけではなく、マウス個体レベルでVNUT阻害作用を持ち、糖代謝を改善することを既に実証しており、引き続きVNUT阻害薬のNASH治療薬としての蓋然性を生体レベルで検証することは今後の医療の発展に貢献できると考えられた。