Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells.
Tanshinone IIA, one of the most pharmacologically bioactive phytochemicals isolated from Salvia miltiorrhiza Bunge, possesses several biological activities such as anti-inflammation, anti-cancer, neuroprotection and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effect of tanshinone IIA in hepatic cells. We demonstrated that tanshinone IIA significantly increased the amount of low-density lipoprotein receptor (LDLR) and LDL uptake activity in HepG2 cells at the post-transcriptional regulation. We further demonstrated that tanshinone IIA inhibited the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA and mature protein, which may lead to an increase the cell-surface LDLR in hepatic cells. We further identified a regulatory DNA element involved in the tanshinone IIA-mediated PCSK9 down-regulation, which is located between the -411 and -336 positions of the PCSK9 promoter. Moreover, we found that tanshinone IIA markedly increased the nuclear forkhead box O3a (FoxO3a) level, enhanced FoxO3a/PCSK9 promoter complexes formation and decreased the PCSK9 promoter binding capacity of hepatocyte nuclear factor 1α (HNF-1α), resulting in suppression of PCSK9 gene expression. Finally, we found that the statin-induced PCSK9 overexpression was attenuated and the LDLR activity was elevated in a synergic manner by combination of tanshinone IIA treatment in HepG2 cells. Overall, our results reveal that the tanshinone IIA modulates LDLR level and activity via down-regulation of PCSK9 expression in hepatic cells. Our current findings provide a molecular basis of tanshinone IIA to develop PCSK9 inhibitors for cholesterol management.
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
Hung-Chen
HC
Chen
Center of Medical Genetics, Buddhist Tzu Chi General Hospital, Hualien, Taiwan.
Pei-Yi
PY
Chen
Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.
Ming-Jiuan
MJ
Wu
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
Mi-Hsueh
MH
Tai
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
Jui-Hung
JH
Yen
D045784:Abietanes / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics
D045784:Abietanes; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; C021751:tanshinone; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9