2. Academic Validation
  3. Ligustilide covalently binds to Cys129 of HMGCS1 to ameliorate dyslipidemia

Ligustilide covalently binds to Cys129 of HMGCS1 to ameliorate dyslipidemia

  • Biomed Pharmacother. 2023 Aug 12;166:115323. doi: 10.1016/j.biopha.2023.115323.
Kaixue Zhang 1,  Fukui Shen 1,  Wei Lei 2,  Yanqi Han 3,  Xiaoyao Ma 1,  Yujie Lu 1,  Yuanyuan Hou 1,  Wenjuan Liu 4,  Min Jiang 5,  Tiejun Zhang 3,  Gang Bai 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, PR China.
  • 2 Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
  • 3 State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Key Laboratory of Quality markers of Traditional Chinese Medicine, Tianjin Institute of Pharmaceutical Research, Tianjin 300462, PR China.
  • 4 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, PR China. Electronic address: liuwenjuan@nankai.edu.cn.
  • 5 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, PR China. Electronic address: minjiang@nankai.edu.cn.
PMID: 37579692 DOI: 10.1016/j.biopha.2023.115323
Abstract

Dyslipidemia is characterized by elevated levels of total Cholesterol and triglycerides in serum, and has become the primary human health killer because of the major risk factors for cardiovascular diseases. Although there exist plenty of drugs for dyslipidemia, the number of patients who could benefit from lipid-lowering drugs still remains a concern. Ligustilide (Lig), a natural phthalide derivative, was reported to regulate lipid metabolic disorders. However, its specific targets and underlying molecular mechanism are still unclear. In this study, we found that Lig alleviated high fat diet-induced dyslipidemia by inhibiting Cholesterol biosynthesis. Furthermore, a series of chemical biological analysis methods were used to identify its target protein for regulating lipid metabolism. Collectively, 3-hydroxy-3-methylglutaryl coenzyme A synthetase 1 (HMGCS1) of hepatic cells was identified as a target for Lig to regulate lipid metabolism. The mechanistic study confirmed that Lig irreversibly binds to Cys129 of HMGCS1 via its metabolic intermediate 6,7-epoxyligustilide, thereby reducing Cholesterol synthesis and improving lipid metabolism disorders. These findings not only systematically elucidated the lipid-lowering mechanism of Lig, but also provided a new structural compound for the treatment of dyslipidemia.

Keywords

Covalent inhibitor; Dyslipidemia; HMGCS1; Ligustilide; Lipid metabolism.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z