Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes.
The purpose of this study was to determine whether bile acids (BAs) modulate hepatic pro-protein convertase subtilisin/kexin 9 (PCSK9) gene expression. Immortalized human hepatocytes were treated with various BAs. Chenodeoxycholic acid (CDCA) treatment specifically decreased both PCSK9 mRNA and protein contents. Moreover, activation of the BA-activated farnesoid X receptor (FXR) by its synthetic specific agonist GW4064 also decreased PCSK9 expression. Of functional relevance, coadministration of CDCA counteracted the statin-induced PCSK9 expression, leading to a potentiation of LDL receptor activity. This study suggests that a transcriptional repression of PCSK9 by CDCA or FXR agonists may potentiate the hypolipidemic effect of statins.
Langhi
Cédric
C
INSERM, U915, CHU Hôtel Dieu, NORD, Nantes F-44000, France.
Le May
Cédric
C
Kourimate
Sanae
S
Caron
Sandrine
S
Staels
Bart
B
Krempf
Michel
M
Costet
Philippe
P
Cariou
Bertrand
B
D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000819:agonists*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011973:Receptors, LDL / Q000819:agonists / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists*; D014158:Transcription, Genetic / Q000187:drug effects*; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007555:Isoxazoles; D017035:Pravastatin; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D012697:Serine Endopeptidases; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C472125:PCSK9 protein, human; C412815:GW 4064