Molecular mechanisms underlying hepatic VLDL secretion induced by extracellular ATP.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K17653
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Kurume University
• Principal Investigator: Hasuzawa Nao 久留米大学, 医学部, 講師 (00837908)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: MASLD / MASH / VLDL / ATP / VNUT / メタボリックシンドローム

Outline of Final Research Achievements

Vesicular nucleotide transporter (VNUT) is responsible for ATP vesicular secretion. We previously reported that VNUT is involved in the regulation of both inflammation and metabolism in the liver and that its inhibitors suppress VLDL secretion and the development of steatohepatitis. The present study aimed to elucidate the molecular mechanisms of ATP vesicle secretion in hepatocytes and to explore the vicious cycle between hepatic fat accumulation and excessive VLDL secretion. We found that: 1)ATP secretion in hepatocytes is dependent on Ca2+ influx, and a rise in glucose or fatty acid levels. 2)Eicosapentaenoic acid deconjugates vesicular membrane potential and inhibits ATP secretion. 3)A novel VNUT inhibitor was found, which shows inhibitory effects on steatohepatitis and liver fibrosis, leading us to file a patent.

Free Research Field

内分泌代謝学

Academic Significance and Societal Importance of the Research Achievements

代謝機能障害関連脂肪肝疾患（MASLD)および同脂肪肝炎(NASH)が引き起こすインスリン抵抗性は、様々な生活習慣病の合併を引き起こすメタボリックシンドロームの根本病態として注目されている。例えば動脈硬化の原因になる高LDLコレステロール血症は、肝臓におけるVLDLの合成及び分泌の亢進が原因となる。本研究では細胞内にエネルギー供給するATPがVNUTというトランスポーターを介して肝臓で細胞外に分泌されると、炎症とVLDL分泌を引き起こすメカニズムに着目し研究を行った。ATPの細胞外分泌を抑制する新たなVNUT阻害薬を発見し、そのMASLD・MASH抑制効果を証明し、特許を出願した。