Zheng Zu-Guo, Zhang Yi-Ping, Zhang Xiao-Yu, Qin Meng-Yao, Xu Yin-Yue, Wu He, Liu Run-Qing, Wu Qiu-Yi, Wang Ming-Su, Zhang Chong, Zheng Yue-Qin, Dai Jian-Ye, Li Ping, Yang Hua
State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
Cell Rep. 2025 Jan 28;44(1):115203. doi: 10.1016/j.celrep.2024.115203. Epub 2025 Jan 11.
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.
甾醇作用于甾醇感应结构域（SSD）蛋白以降低胆固醇以及循环和肝脏甘油三酯水平，但其机制尚不清楚。在本研究中，我们确定酰基辅酶A（CoA）合成酶长链家族成员1（ACSL1）是麦角甾醇（ES）的直接靶点。ACSL1的C末端结构域经历从封闭到开放的构象变化，并且ES可能作用于ACSL1的乙酰辅酶A合成酶样结构域1（ASLD1）中的药物结合口袋，以稳定封闭构象并维持其活性。此外，ES主要富集于线粒体中，并通过ACSL1变构激活促进脂肪酸β氧化。构效关系分析揭示了不同结构的甾醇如何与含甾醇感应结构域的蛋白（SCAP）和ACSL1相互作用，解释了它们对脂质代谢的调节作用。此外，我们的研究结果表明，SCAP抑制剂25-羟基胆固醇（25-HC）和ES联合使用比单独使用具有更强的降脂作用。
