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

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...

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Vydané v:	Nature communications Ročník 15; číslo 1; s. 2195 - 14
Hlavní autori:	Yamada, Naoya, Karasawa, Tadayoshi, Ito, Junya, Yamamuro, Daisuke, Morimoto, Kazushi, Nakamura, Toshitaka, Komada, Takanori, Baatarjav, Chintogtokh, Saimoto, Yuma, Jinnouchi, Yuka, Watanabe, Kazuhisa, Miura, Kouichi, Yahagi, Naoya, Nakagawa, Kiyotaka, Matsumura, Takayoshi, Yamada, Ken-ichi, Ishibashi, Shun, Sata, Naohiro, Conrad, Marcus, Takahashi, Masafumi
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 12.03.2024 Nature Publishing Group Nature Portfolio
Predmet:	13 14/19 38/43 49/40 631/80/82 64/60 692/4020/4021/288/2032 692/699/1503/1607 7-Dehydrocholesterol reductase 82/1 82/58 82/80 Ablation Acetaminophen Animals Biosynthesis Cholesterol Cyclodextrins Electron paramagnetic resonance Electron spin Electron spin resonance Electrons Enzymes Ferroptosis Hepatocellular carcinoma Hepatocytes Humanities and Social Sciences Humans Injury prevention Ischemia Liver Liver cancer Liver Diseases Liver failure Metabolites Mice multidisciplinary Oxidation Oxidoreductases Acting on CH-CH Group Donors - metabolism Pathophysiology Reductases Regulatory mechanisms (biology) Reperfusion Science Science (multidisciplinary) Spin resonance Substrate inhibition trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride β-Cyclodextrin
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-46386-6