Novel therapeutic strategy against hyperammonemia based on intervention in regulatory mechanism of bodily protein anabolism and catabolism

2021 Fiscal Year Final Research Report

• Project/Area Number: 17K16285
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Kurume University
• Principal Investigator: FUKUI KAORI 久留米大学, 医学部, 助教 (50771193)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Keywords: 高アンモニア血症 / グルタミノリシス / α-ケトグルタル酸 / ジメチルα-ケトグルタル酸 / 尿素サイクル異常症

Outline of Final Research Achievements

Patients with urea cycle disorders intermittently develop episodes of decompensation with hyperammonemia. Because such an episode is often associated with starvation, we attempted to elucidate the mechanism of such starvation-associated hyperammonemia. Using a cell culture system, we found that glucose starvation increases ammonia production, and that it is associated with enhanced glutaminolysis. These results led us to focus on α-ketoglutarate (AKG), a glutamate dehydrogenase inhibitor and a major anaplerotic metabolite. We found that dimethyl αketoglutarate (DKG), a cell-permeable AKG analog, mitigates ammonia production primarily by reducing glutaminolytic flux. We also verified that DKG reduces ammonia also in in vivo animal models. Thus, AKG itself or cell-permeable forms of AKG are feasible candidates for a novel hyperammonemia treatment.

Free Research Field

先天代謝異常症

Academic Significance and Societal Importance of the Research Achievements

高アンモニア血症の治療法は現在、産生されたアンモニアを除去することが主体となっている。いっぽう我々は飢餓と高アンモニア血症の関係に注目し、アンモニア産生の抑制に重点をおいて研究を行った。その結果、飢餓により亢進したグルタミノリシスを抑制し、かつTCAサイクルへの基質補充を行うことで、高アンモニア血症を是正できることを示した。これは高アンモニア血症の新奇、かつ現実的な治療戦略となりうる。