Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1
Summary: Sterols target sterol-sensing domain (SSD) proteins to lower cholesterol and circulating and hepatic triglyceride levels, but the mechanism remains unclear. In this study, we identify acyl-coenzyme A (CoA) synthetase long-chain family member 1 (ACSL1) as a direct target of ergosterol (ES)....
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724015547 |
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| author | Zu-Guo Zheng Yi-Ping Zhang Xiao-Yu Zhang Meng-Yao Qin Yin-Yue Xu He Wu Run-Qing Liu Qiu-Yi Wu Ming-Su Wang Chong Zhang Yue-Qin Zheng Jian-Ye Dai Ping Li Hua Yang |
| author_facet | Zu-Guo Zheng Yi-Ping Zhang Xiao-Yu Zhang Meng-Yao Qin Yin-Yue Xu He Wu Run-Qing Liu Qiu-Yi Wu Ming-Su Wang Chong Zhang Yue-Qin Zheng Jian-Ye Dai Ping Li Hua Yang |
| author_sort | Zu-Guo Zheng |
| collection | DOAJ |
| description | Summary: Sterols target sterol-sensing domain (SSD) proteins to lower cholesterol and circulating and hepatic triglyceride levels, but the mechanism remains unclear. In this study, we identify acyl-coenzyme A (CoA) synthetase long-chain family member 1 (ACSL1) as a direct target of ergosterol (ES). The C-terminal domain of ACSL1 undergoes conformational changes from closed to open, and ES may target the drug-binding pocket in the acetyl-CoA synthetase-like domain 1 (ASLD1) of ACSL1 to stabilize the closed conformation and maintain its activity. Moreover, ES is mainly enriched in the mitochondria and promotes fatty acid β-oxidation through ACSL1 allosteric activation. Structure-activity relationship analysis reveals how different structural sterols interact with the sterol-sensing domain-containing protein (SCAP) and ACSL1, explaining their regulatory effects on lipid metabolism. Moreover, our findings reveal that the combination of SCAP inhibitor 25-hydroxycholesterol (25-HC) and ES has a stronger lipid-lowering effect than alone. |
| format | Article |
| id | doaj-art-61a34b44fadf42d9bdb6af3a690d0bea |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-61a34b44fadf42d9bdb6af3a690d0bea2025-01-12T05:24:53ZengElsevierCell Reports2211-12472025-01-01441115203Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1Zu-Guo Zheng0Yi-Ping Zhang1Xiao-Yu Zhang2Meng-Yao Qin3Yin-Yue Xu4He Wu5Run-Qing Liu6Qiu-Yi Wu7Ming-Su Wang8Chong Zhang9Yue-Qin Zheng10Jian-Ye Dai11Ping Li12Hua Yang13State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Corresponding authorState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaCollaborative Innovation Center for Northwestern Chinese Medicine & School of Pharmacy, Lanzhou University, Lanzhou, Gansu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, ChinaCollaborative Innovation Center for Northwestern Chinese Medicine & School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China; Corresponding authorState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Corresponding authorState Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Corresponding authorSummary: Sterols target sterol-sensing domain (SSD) proteins to lower cholesterol and circulating and hepatic triglyceride levels, but the mechanism remains unclear. In this study, we identify acyl-coenzyme A (CoA) synthetase long-chain family member 1 (ACSL1) as a direct target of ergosterol (ES). The C-terminal domain of ACSL1 undergoes conformational changes from closed to open, and ES may target the drug-binding pocket in the acetyl-CoA synthetase-like domain 1 (ASLD1) of ACSL1 to stabilize the closed conformation and maintain its activity. Moreover, ES is mainly enriched in the mitochondria and promotes fatty acid β-oxidation through ACSL1 allosteric activation. Structure-activity relationship analysis reveals how different structural sterols interact with the sterol-sensing domain-containing protein (SCAP) and ACSL1, explaining their regulatory effects on lipid metabolism. Moreover, our findings reveal that the combination of SCAP inhibitor 25-hydroxycholesterol (25-HC) and ES has a stronger lipid-lowering effect than alone.http://www.sciencedirect.com/science/article/pii/S2211124724015547CP: Metabolism |
| spellingShingle | Zu-Guo Zheng Yi-Ping Zhang Xiao-Yu Zhang Meng-Yao Qin Yin-Yue Xu He Wu Run-Qing Liu Qiu-Yi Wu Ming-Su Wang Chong Zhang Yue-Qin Zheng Jian-Ye Dai Ping Li Hua Yang Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1 Cell Reports CP: Metabolism |
| title | Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1 |
| title_full | Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1 |
| title_fullStr | Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1 |
| title_full_unstemmed | Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1 |
| title_short | Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1 |
| title_sort | ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β oxidation by activating mitochondrial acsl1 |
| topic | CP: Metabolism |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724015547 |
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