2022 Fiscal Year Final Research Report

Development of a new trategy for low HDL in homogygous FH patients

Research Project

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Project/Area Number	20K08439
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 53020:Cardiology-related
Research Institution	National Defense Medical College
Principal Investigator	Ikewaki Katsunori 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 教授 (40287199)
Co-Investigator(Kenkyū-buntansha)	小倉正恒国立研究開発法人国立循環器病研究センター, 研究所, 室長 (30532486) 末永由美子防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 助教 (30815337) 佐々木誠防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 助教 (60837251)
Project Period (FY)	2020-04-01 – 2023-03-31
Keywords	FH / HDL / apoA-I / apoA-II / stable isotope / catabolism
Outline of Final Research Achievements	FH homozygote is considered to be very high risk for atherosclerosis. Low HDL-C contribute in part for the increased atherosclerosis risk. Therefore, we aimed to elucidate kinetic pathophysiology for low HDL. We performed in vivo kinetic studies using endogenously-labeled stable isotope in 7 FH homozygotes. Kinetic studies revealed that fractional catabolic rates of apoA-I and apoA-II, major constituents of HDL, were markedly increased by about 50% as compared with control subjects with relatively unchanged synthetic rates. Therefore, low HDL levels was primarily due to increased catabolism in FH homozygotes. These findings may imply that therapy such as CETP inhibitors can normalized increased catabolic rates, thereby normalizing HDL-C in FH homozygotes. This may be a novel therapeutic strategy for treatment-resistant homozygous FH patients.
Free Research Field	lipid metabolism
Academic Significance and Societal Importance of the Research Achievements	FH homozygotes needs early and effective treatment. The present study discovered that increased catabolic rate caused low HDL-C, another additive atheroscleritic risk. Based on our findings, we may develop a new therapy to nomalize catbolism to reduce the risk in FH homozygotes.