Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products
A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:87 |
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| Enthalten in: |
Journal of natural products - 87(2024), 2 vom: 23. Feb., Seite 322-331 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fang, Yuwei [VerfasserIn] |
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| Links: |
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| Themen: |
97C5T2UQ7J |
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| Anmerkungen: |
Date Completed 26.02.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jnatprod.3c01029 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα | ||
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| 700 | 1 | |a She, Jianglian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Gu, Tanwei |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Danni |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Xiaowei |e verfasserin |4 aut | |
| 700 | 1 | |a Yi, Xiangxi |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Chenghai |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yonghong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cuixian |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Lan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xuefeng |e verfasserin |4 aut | |
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