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.