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2021 Fiscal Year Final Research Report

Liver specific regulation mechanism of ferroptosis

Research Project

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Project/Area Number 20K22940
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0904:Internal medicine of the bio-information integration and related fields
Research InstitutionJichi Medical University

Principal Investigator

Yamada Naoya  自治医科大学, 医学部, ポスト・ドクター (50611787)

Project Period (FY) 2020-09-11 – 2022-03-31
Keywordsフェロトーシス / 細胞死 / 鉄 / 脂質酸化 / 肝虚血再灌流障害 / オキシステロール
Outline of Final Research Achievements

We identified 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a novel regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppressed lipid peroxidation and ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increased its substrate, 7-dehydrocholesterol (7-DHC), and extrinsic 7-DHC supplementation in turn suppressed ferroptosis. 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), was increased by a ferroptosis inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition was driven by intracellular 7-DHC as a radical scavenger. AY9944 suppressed ferroptosis in murine primary hepatocytes in vitro and systemic administration of AY9944 inhibited hepatic ischemia-reperfusion injury in vivo. In conclusion, DHCR7 inhibition is a potential therapeutic option for ferroptosis-related liver diseases.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

近年、新たな細胞死であるフェロトーシスと様々な疾患への関与が相次いで報告され、注目を集めている。肝臓では、近年患者数の増加が問題視されている非アルコール性脂肪性肝炎やアルコール性肝炎、急性肝不全の原因であるアセトアミノフェン肝障害、肝虚血再灌流障害などへの関与が報告されている。本研究では、肝臓に特異的なフェロトーシスの制御因子として、コレステロール合成酵素の1つであるDHCR7を同定した。DHCR7の阻害剤は肝細胞のフェロトーシスを抑制し、肝虚血再灌流障害を軽減した。これらから、DHCR7を標的とした治療はフェロトーシス関連肝疾患に有効であると期待される。

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Published: 2023-01-30  

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