| RRC ID |
79154
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| 著者 |
Yamada N, Karasawa T, Ito J, Yamamuro D, Morimoto K, Nakamura T, Komada T, Baatarjav C, Saimoto Y, Jinnouchi Y, Watanabe K, Miura K, Yahagi N, Nakagawa K, Matsumura T, Yamada KI, Ishibashi S, Sata N, Conrad M, Takahashi M.
|
| タイトル |
Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis.
|
| ジャーナル |
Nat Commun
|
| 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.
|
| 巻・号 |
15(1)
|
| ページ |
2195
|
| 公開日 |
2024-3-12
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| DOI |
10.1038/s41467-024-46386-6
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| PII |
10.1038/s41467-024-46386-6
|
| PMID |
38472233
|
| PMC |
PMC10933264
|
| MeSH |
Animals
Ferroptosis*
Humans
Liver Diseases*
Mice
Oxidoreductases Acting on CH-CH Group Donors* / metabolism
trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride
|
| リソース情報 |
| 遺伝子材料 |
CSIV-TRE-RfA-CMV-KT (RDB12876) |
