Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine
Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine
复制标题
DOI：
10.1161/01.atv.0000181761.16341.2b
复制
发表时间：
2005-10-01
影响因子：
8.7
通讯作者：
Liu, JW
中科院分区：
文献类型：
--
作者：
Abidi, P;Zhou, Y;Liu, JW
目的：我们最近的研究发现小檗碱（BBR）是一种新型的降胆固醇药物，通过稳定mRNA上调低密度脂蛋白（LDL）受体的表达。在这里，我们研究了BBR对LDL受体（LDLR）messenger.Methods和Results的调节作用的机制-我们表明，细胞外信号调节激酶（ERK）信号通路主要是由BBR衰减LDLR mRNA在HepG 2细胞中的衰减。使用不同的报告结构，我们证明，BBR影响LDLR mRNA的稳定性，完全通过3'非翻译区（UTR）在ERK依赖的方式，这种稳定作用是更突出的肝细胞比非肝细胞系。与BBR相反，胆汁酸鹅去氧胆酸的mRNA稳定作用是通过LDLR编码序列介导的，而LDLR mRNA的5' UTR、3' UTR和编码序列都与佛波醇12-肉豆蔻酸酯13-乙酸酯的作用有关。通过进行UV交联和SDS-PAGE，我们鉴定了2个52和42 kDa的细胞质蛋白，它们以BBR诱导和ERK依赖的方式特异性结合LDLR 3' UTR。结论-这些新的发现表明，BBR诱导的LDLR mRNA的稳定是由ERK信号通路通过顺式-3 'UTR和mRNA结合蛋白的调节序列，其是该信号级联的下游效应物。
Objective - Our recent studies identified berberine (BBR) as a novel cholesterol-lowering drug that upregulates low-density lipoprotein (LDL) receptor expression through mRNA stabilization. Here, we investigated mechanisms underlying regulatory effects of BBR on LDL receptor ( LDLR) messenger.Methods and Results - We show that the extracellular signal-regulated kinase (ERK) signaling pathway is used primarily by BBR to attenuate the decay of LDLR mRNA in HepG2 cells. Using different reporter constructs, we demonstrate that BBR affects LDLR mRNA stability entirely through 3' untranslated region (UTR) in an ERK-dependent manner, and this stabilizing effect is more prominent in liver-derived cells than nonhepatic cell lines. In contrast to BBR, the mRNA stabilizing effect of bile acid chenodeoxycholic acid is mediated through the LDLR coding sequence, whereas the 5' UTR, 3'UTR, and the coding sequence of LDLR mRNA are all implicated in the action of phorbol 12-myristate 13-acetate. By performing UV cross-linking and SDS-PAGE, we identify 2 cytoplasmic proteins of 52 and 42 kDa that specifically bind to the LDLR 3' UTR in BBR-inducible and ERK-dependent manners.Conclusions - These new findings demonstrate that the BBR-induced stabilization of LDLR mRNA is mediated by the ERK signaling pathway through interactions of cis-regulatory sequences of 3'UTR and mRNA binding proteins that are downstream effectors of this signaling cascade.