title: Curcumin enhances cell-surface LDLR level and promotes LDL uptake through downregulation of PCSK9 gene expression in HepG2 cells.
abstract: METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan.
authors.forename: Mi-Hsueh
authors.initials: MH
authors.lastname: Tai
authors.forename: Po-Kong
authors.initials: PK
authors.lastname: Chen
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chen
authors.forename: Ming-Jiuan
authors.initials: MJ
authors.lastname: Wu
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism*; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000188:drug therapy; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D008078:Cholesterol, LDL; D051538:Hepatocyte Nuclear Factor 1-alpha; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D003474:Curcumin
keywords: Curcumin; HNF-1α; Hypercholesterolemia; LDLR; PCSK9