Li Huihui, Li Jun, Zhang Xianjing, Li Jiaomeng, Xi Cong, Wang Wenqiong, Lu Youli, Xuan Lijiang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
University of Chinese Academy of Sciences, Beijing 100049, P.R. China.
Exp Ther Med. 2021 Dec;22(6):1381. doi: 10.3892/etm.2021.10817. Epub 2021 Sep 28.
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 mRNA transcription but lengthened the half-life of mRNA by activating ERK protein in cells. Euphornin L decreased the secretion of PCSK9 protein and alleviated PCSK9-mediated LDLR protein degradation. 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 mRNA and PCSK9 protein, and represented an active compound for lipid-lowering drug development.
我们之前的研究确定了优福宁L是高脂饮食喂养的金黄地鼠中一种具有活性的降脂化合物。本研究的目的是探究优福宁L降脂作用的潜在机制。通过DiI-LDL摄取试验评估了优福宁L在HepG2细胞中的作用，发现其可增加LDL摄取和LDLR蛋白水平。RNA干扰试验表明其LDL摄取作用依赖于LDLR。双荧光素酶报告基因和mRNA稳定性试验显示，优福宁L对mRNA转录影响不大，但通过激活细胞中的ERK蛋白延长了mRNA的半衰期。优福宁L减少了PCSK9蛋白的分泌，减轻了PCSK9介导的LDLR蛋白降解。用优福宁L（30 mg/kg/天）处理3周的仓鼠实验证实了这些发现。肝组织中的LDLR蛋白水平上调，而血清中的PCSK9蛋白水平下调。总之，本研究表明优福宁L通过对mRNA和PCSK9蛋白的双重调节增加了LDLR蛋白水平，是一种用于降脂药物开发的活性化合物。
