Curcumin enhances cell-surface LDLR level and promotes LDL uptake through downregulation of PCSK9 gene expression in HepG2 cells

Mol Nutr Food Res. 2014 Nov;58(11):2133-45. doi: 10.1002/mnfr.201400366. Epub 2014 Sep 19.

Abstract

Scope: Curcumin has been demonstrated as having numerous desirable characteristics, such as antioxidant, anti-inflammatory, and antiatherogenic activities. We report the hypocholesterolemic effect and molecular mechanism of curcumin.

Methods and results: We found that curcumin enhanced LDL receptor (LDLR) level on the cell surface, as well as LDLR activity; however, LDLR transcription and mRNA stability were not affected. Furthermore, we found that proprotein convertase subtilisin/kexin type 9 (PCSK9) gene was downregulated at the transcriptional level by curcumin, leading to an increase in LDL uptake in HepG2 cells. The curcumin-responsive element of the PCSK9 promoter, a binding site for hepatocyte nuclear factor 1α (HNF-1α), was also identified. We demonstrated that curcumin reduced the nuclear abundance of hepatocyte nuclear factor 1α, resulting in its attenuated interaction with the PCSK9 promoter and leading to a downregulation of PCSK9 expression. Finally, we showed that curcumin decreased the statin-induced PCSK9 expression and potentially synergized with statin administration.

Conclusion: Current results indicate that curcumin suppression of PCSK9 expression is associated with increases in cell-surface LDLR and LDLR activity in hepatic cells and it acts in a molecular mechanism that is distinct from the statins. Curcumin exhibits hypolipidemic activity and may serve as a useful supplement to statin treatment for hypercholesterolemia.

Keywords: Curcumin; HNF-1α; Hypercholesterolemia; LDLR; PCSK9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cholesterol, LDL / metabolism*
  • Curcumin / chemistry
  • Curcumin / pharmacology*
  • Down-Regulation / drug effects*
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hypercholesterolemia / drug therapy
  • Proprotein Convertase 9
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Transcription, Genetic

Substances

  • Cholesterol, LDL
  • Hepatocyte Nuclear Factor 1-alpha
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • RNA, Messenger
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
  • Curcumin