Ergosterol alleviates hepatic steatosis and insulin resistance via promoting fatty acid β-oxidation by activating mitochondrial ACSL1

  • Cell Rep. 2025 Jan 28;44(1):115203. doi: 10.1016/j.celrep.2024.115203.
Zu-Guo Zheng  1 ,  Yi-Ping Zhang  2 ,  Xiao-Yu Zhang  2 ,  Meng-Yao Qin  3 ,  Yin-Yue Xu  2 ,  He Wu  2 ,  Run-Qing Liu  2 ,  Qiu-Yi Wu  2 ,  Ming-Su Wang  2 ,  Chong Zhang  2 ,  Yue-Qin Zheng  2 ,  Jian-Ye Dai  4 ,  Ping Li  5 ,  Hua Yang  6
Affiliations
  • 1. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: [email protected].
  • 2. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
  • 3. Collaborative Innovation Center for Northwestern Chinese Medicine & School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China.
  • 4. Collaborative Innovation Center for Northwestern Chinese Medicine & School of Pharmacy, Lanzhou University, Lanzhou, Gansu, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address: [email protected].
PMID: 39799570 DOI: 10.1016/j.celrep.2024.115203
Abstract

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.

Keywords
ACSL1; CP: Metabolism; SCAP/SREBP; ergosterol; hepatic steatosis; insulin resistance.
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