Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Nature communications - 15(2024), 1 vom: 12. März, Seite 2195 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Yamada, Naoya [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
366-93-8 |
|---|
| Anmerkungen: |
Date Completed 14.03.2024 Date Revised 15.03.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41467-024-46386-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36961951X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36961951X | ||
| 003 | DE-627 | ||
| 005 | 20240315233641.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240313s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-024-46386-6 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1330.xml |
| 035 | |a (DE-627)NLM36961951X | ||
| 035 | |a (NLM)38472233 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Yamada, Naoya |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.03.2024 | ||
| 500 | |a Date Revised 15.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a 7-dehydrocholesterol reductase |2 NLM | |
| 650 | 7 | |a EC 1.3.1.21 |2 NLM | |
| 650 | 7 | |a trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride |2 NLM | |
| 650 | 7 | |a 366-93-8 |2 NLM | |
| 650 | 7 | |a Oxidoreductases Acting on CH-CH Group Donors |2 NLM | |
| 650 | 7 | |a EC 1.3.- |2 NLM | |
| 700 | 1 | |a Karasawa, Tadayoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Ito, Junya |e verfasserin |4 aut | |
| 700 | 1 | |a Yamamuro, Daisuke |e verfasserin |4 aut | |
| 700 | 1 | |a Morimoto, Kazushi |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Toshitaka |e verfasserin |4 aut | |
| 700 | 1 | |a Komada, Takanori |e verfasserin |4 aut | |
| 700 | 1 | |a Baatarjav, Chintogtokh |e verfasserin |4 aut | |
| 700 | 1 | |a Saimoto, Yuma |e verfasserin |4 aut | |
| 700 | 1 | |a Jinnouchi, Yuka |e verfasserin |4 aut | |
| 700 | 1 | |a Watanabe, Kazuhisa |e verfasserin |4 aut | |
| 700 | 1 | |a Miura, Kouichi |e verfasserin |4 aut | |
| 700 | 1 | |a Yahagi, Naoya |e verfasserin |4 aut | |
| 700 | 1 | |a Nakagawa, Kiyotaka |e verfasserin |4 aut | |
| 700 | 1 | |a Matsumura, Takayoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Yamada, Ken-Ichi |e verfasserin |4 aut | |
| 700 | 1 | |a Ishibashi, Shun |e verfasserin |4 aut | |
| 700 | 1 | |a Sata, Naohiro |e verfasserin |4 aut | |
| 700 | 1 | |a Conrad, Marcus |e verfasserin |4 aut | |
| 700 | 1 | |a Takahashi, Masafumi |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 15(2024), 1 vom: 12. März, Seite 2195 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2024 |g number:1 |g day:12 |g month:03 |g pages:2195 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-024-46386-6 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2024 |e 1 |b 12 |c 03 |h 2195 | ||