Epigallocatechin gallate induces an up-regulation of LDL receptor accompanied by a reduction of PCSK9 via the annexin A2-independent pathway in HepG2 cells.
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.



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.



Annexin A2 possesses an essential function for the basal LDLR expression in HepG2 cells. But, EGCG induces the suppression of PCSK9 accompanied by an up-regulation of LDLR in an annexin A2-independent manner. EGCG attenuates the statin-induced an increase in PCSK9 level.
Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, Japan.
Kohei
K
Kitamura
Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, Japan.
Yudai
Y
Okada
Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, Japan.
Kenji
K
Okada
Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, Japan.
Yuya
Y
Kawaguchi
Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, Japan.
Satoshi
S
Nagaoka
D017306:Annexin A2 / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000493:pharmacokinetics; D008148:Lovastatin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C472822:ANXA2 protein, human; D017306:Annexin A2; C573412:LDLR protein, human; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002392:Catechin; D008148:Lovastatin; C045651:epigallocatechin gallate; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
Annexin A2; Epigallocatechin gallate; HepG2; LDL receptor; PCSK9