Epigallocatechin gallate induces an up-regulation of LDL receptor accompanied by a reduction of PCSK9 via the annexin A2-independent pathway in HepG2 cells
Epigallocatechin gallate induces an up-regulation of LDL receptor accompanied by a reduction of PCSK9 via the annexin A2-independent pathway in HepG2 cells
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DOI：
10.1002/mnfr.201600836
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发表时间：
2017-08-01
影响因子：
5.2
通讯作者：
Nagaoka, Satoshi
中科院分区：
文献类型：
--
作者：
Kitamura, Kohei;Okada, Yudai;Nagaoka, Satoshi
范围：在动物研究中，绿茶中的主要儿茶素-表没食子儿茶素没食子酸酯(EGCG)已被证明可以改善胆固醇代谢。然而，EGCG在这些功能中的分子机制还没有完全被理解。本研究旨在阐明EGCG影响人肝癌细胞胆固醇代谢的分子机制。方法和结果：我们发现EGCG诱导细胞外蛋白原转换酶枯草杆菌/可信9(PCSK9)水平降低，同时低密度脂蛋白受体(LDLR)表达上调。EGCG诱导的LDLR表达上调是通过细胞外信号调节激酶(ERK)信号通路实现的。此外，我们还发现EGCG诱导了细胞外PCSK9蛋白水平的早期显著降低。而EGCG对PCSK9基因的表达及细胞内PCSK9蛋白水平无明显影响。Annexin A2基因敲除后可影响基础LDLR的表达，但不影响EGCG诱导的细胞外PCSK9蛋白水平的降低或LDLR的上调。结论：Annexin A2对细胞LDLR的基础表达具有重要作用。但是，EGCG2以非依赖的方式抑制PCSK9，同时上调LDLR。EGCG可减弱他汀类药物诱导的PCSK9水平升高。
Scope: In animal studies, epigallocatechin gallate (EGCG), the dominant catechin in green tea, has been shown to improve cholesterol metabolism. However, the molecular mechanisms of EGCG underlying these functions have not been fully understood. In this study, we aimed to clarify the molecular mechanisms of the effect of EGCG on cholesterol metabolism mainly in HepG2 cells.Methods and results: We found that EGCG induced a reduction of the extracellular proprotein convertase subtilisin/kexin 9 (PCSK9) level accompanied by an up-regulation of the LDL receptor (LDLR) in HepG2 cells. The EGCG-induced up-regulation of LDLR occurred via the extracellular signal-regulated kinase (ERK) signaling pathway. Moreover, we showed that EGCG induced a significant early reduction of the extracellular PCSK9 protein level. However, there were no significant changes in the PCSK9 mRNA and the intracellular PCSK9 protein levels induced by EGCG. Annexin A2 knockdown affected the basal LDLR expression and did not affect the EGCG-induced reduction of the extracellular PCSK9 protein level or the up-regulation of LDLR.Conclusion: Annexin A2 possesses an essential function for the basal LDLR expression in HepG2 cells. But, EGCGinduces the suppression of PCSK9 accompanied by an up-regulation of LDLR in an annexin A2-independentmanner. EGCG attenuates the statin-induced an increase in PCSK9 level.