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Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis

Author

Listed:
  • Naoya Yamada

    (Jichi Medical University
    Jichi Medical University
    Molecular Target and Therapeutics Center, Helmholtz Munich)

  • Tadayoshi Karasawa

    (Jichi Medical University)

  • Junya Ito

    (Tohoku University)

  • Daisuke Yamamuro

    (Jichi Medical University)

  • Kazushi Morimoto

    (Kyushu University, Fukuoka)

  • Toshitaka Nakamura

    (Molecular Target and Therapeutics Center, Helmholtz Munich)

  • Takanori Komada

    (Jichi Medical University)

  • Chintogtokh Baatarjav

    (Jichi Medical University)

  • Yuma Saimoto

    (Kyushu University, Fukuoka)

  • Yuka Jinnouchi

    (Kyushu University, Fukuoka)

  • Kazuhisa Watanabe

    (Jichi Medical University)

  • Kouichi Miura

    (Jichi Medical University)

  • Naoya Yahagi

    (Jichi Medical University)

  • Kiyotaka Nakagawa

    (Tohoku University)

  • Takayoshi Matsumura

    (Jichi Medical University
    Jichi Medical University)

  • Ken-ichi Yamada

    (Kyushu University, Fukuoka)

  • Shun Ishibashi

    (Jichi Medical University)

  • Naohiro Sata

    (Jichi Medical University)

  • Marcus Conrad

    (Molecular Target and Therapeutics Center, Helmholtz Munich)

  • Masafumi Takahashi

    (Jichi Medical University)

Abstract

Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.

Suggested Citation

  • Naoya Yamada & Tadayoshi Karasawa & Junya Ito & Daisuke Yamamuro & Kazushi Morimoto & Toshitaka Nakamura & Takanori Komada & Chintogtokh Baatarjav & Yuma Saimoto & Yuka Jinnouchi & Kazuhisa Watanabe &, 2024. "Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46386-6
    DOI: 10.1038/s41467-024-46386-6
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    References listed on IDEAS

    as
    1. Daqian Xu & Zheng Wang & Yan Xia & Fei Shao & Weiya Xia & Yongkun Wei & Xinjian Li & Xu Qian & Jong-Ho Lee & Linyong Du & Yanhua Zheng & Guishuai Lv & Jia-shiun Leu & Hongyang Wang & Dongming Xing & T, 2020. "The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis," Nature, Nature, vol. 580(7804), pages 530-535, April.
    2. Yuta Matsuoka & Masatomo Takahashi & Yuki Sugiura & Yoshihiro Izumi & Kazuhiro Nishiyama & Motohiro Nishida & Makoto Suematsu & Takeshi Bamba & Ken-ichi Yamada, 2021. "Structural library and visualization of endogenously oxidized phosphatidylcholines using mass spectrometry-based techniques," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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