Euphornin L promotes lipid clearance by dual regulation of LDLR and PCSK9

Huihui Li; Jun Li; Xianjing Zhang; Jiaomeng Li; Cong Xi; Wenqiong Wang; Youli Lu; Lijiang Xuan

doi:10.3892/etm.2021.10817

Euphornin L promotes lipid clearance by dual regulation of LDLR and PCSK9

Exp Ther Med. 2021 Dec;22(6):1381. doi: 10.3892/etm.2021.10817. Epub 2021 Sep 28.

Authors

Huihui Li^{1

2}, Jun Li^{1

2}, Xianjing Zhang^{1

2}, Jiaomeng Li^{1

2}, Cong Xi^{1

2}, Wenqiong Wang^{1

2}, Youli Lu^{3

4}, Lijiang Xuan^{1

2}

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
² University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
³ Central Laboratory, Shanghai Xuhui Central Hospital/Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200031, P.R. China.
⁴ Shanghai Clinical Research Center, Chinese Academy of Sciences, Shanghai 200031, P.R. China.

Abstract

Our previous study identified euphornin L as an active lipid-lowering compound in high-fat diet-fed Golden Syrian hamsters. The aim of the present study was to investigate the mechanisms underlying the lipid-lowering effects of euphornin L. Euphornin L in HepG2 cells was assessed via DiI-LDL update assays and found to increase LDL-update and LDLR protein levels. RNA interference assays demonstrated that its LDL-update effects were LDLR-dependent. Dual luciferase reporter and mRNA stability assays revealed that euphornin L had little effect on LDLR mRNA transcription but lengthened the half-life of LDLR mRNA by activating ERK protein in cells. Euphornin L decreased the secretion of PCSK9 protein and alleviated PCSK9-mediated LDLR protein degradation. In vivo experiments in hamsters, which were treated with euphornin L (30 mg/kg/day) for 3 weeks, confirmed these findings. LDLR protein levels in liver tissue were upregulated, while PCSK9 protein levels in serum were downregulated. Altogether, the present study demonstrated that euphornin L increased LDLR protein levels by dual regulation of LDLR mRNA and PCSK9 protein, and represented an active compound for lipid-lowering drug development.

Keywords: euphornin L; extracellular signal-regulated kinase protein; lipid-lowering activity; low density lipoprotein receptor; proprotein convertase subtilisin/kexin type 9; secretion.

Grants and funding

Funding: The authors gratefully acknowledge grants from the Drug Innovation Major Project of China (grant no. 2018ZX09735001-002-005), the Personalized Medicines-Molecular Signature-based Drug Discovery and Development Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDA12040335), the National Natural Science Foundation of China (grant no. 81773863) and the Youth Innovation Promotion Association (grant no. 2019284).