Tanshinone IIA Modulates Low Density Lipoprotein Uptake via Down-Regulation of PCSK9 Gene Expression in HepG2 Cells

Abstract

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.

Inhibition of low-density lipoprotein receptor degradation with a cyclic peptide that disrupts the homodimerization of IDOL E3 ubiquitin ligase

“…3e ). While the effect of increased LDLR levels on the transcription of PCSK9 and HMGCoAR are in line with previous reports, 30 we also observed a previously unreported effect on LXRα and LXRβ expression. As IDOL is a target gene of the LXR transcription factors, it is likely that the observed down regulation of these genes is as a consequence of a previously unidentified auto-regulatory circuit for IDOL.…”

A small-molecule inhibitor of PCSK9 transcription ameliorates atherosclerosis through the modulation of FoxO1/3 and HNF1α

“…This strategy was innovative but the development of the active compound was stopped for some competitive reasons [24]. Some natural products, such as berberine (BBR) [50], curcumin [51] and tanshinone IIA [52], have been found to reduce PCSK9 transcription and expression, but none of them have been investigated as PCSK9 inhibitors further, probably due to their wide regulatory effects. Eli Lilly's Open Innovation Drug Discovery (OIDD) platform includes a screening module for PCSK9 synthesis inhibition.…”

Atheroprotective Effects and Molecular Targets of Tanshinones Derived From Herbal Medicine Danshen

“…Clinically, PCSK9 antibodies were approved to treat hyperlipidemia‐associated atherosclerotic CVDs . A recent study has shown that TSN inhibits hepatic PCSK9 expression by increasing the forkhead box O3a binding, while decreasing the binding of hepatocyte nuclear factor 1α to PCSK9 gene promoter, thereby upregulating LDL receptor posttranscriptionally. Due to mixed results on lipid profiles in experimental animals and clinical studies, further elucidation of the effects of TSN on PCSK9 functioning remains to be investigated in experimental models of hyperlipidemia and patients with familial hyperlipidemia.…”