Farnesoid X receptor represses hepatic lipase gene expression.
The farnesoid X receptor (FXR) is a nuclear receptor that regulates gene expression in response to bile acids (BAs). FXR plays a central role in BA, cholesterol, and lipoprotein metabolism. Here, we identify HL, an enzyme involved in the metabolism of remnant and high density lipoproteins, as a novel FXR-regulated gene. The natural FXR ligand, chenodeoxycholic acid (CDCA), downregulates HL gene expression in a dose- and time-dependent manner in human hepatoma HepG2 cells. The nonsteroidal synthetic FXR agonist GW4064 also decreases HL mRNA levels in HepG2 cells and in primary human hepatocytes. Moreover, the decrease of HL mRNA levels after treatment with FXR agonists was associated with a significant decrease in secreted enzymatic activity. In addition, FXR-specific gene silencing using small interfering RNAs demonstrated that CDCA- and GW4064-mediated downregulation of HL transcript levels occurs via an FXR-dependent mechanism. Finally, using transient transfection experiments, it is shown that FXR represses transcriptional activity of a reporter driven by the -698/+13 bp human HL promoter. Taken together, these results identify HL as a new FXR-regulated gene in human liver cells. In view of the role of HL in plasma lipoprotein metabolism, our results further emphasize the central role of FXR in lipid homeostasis.
Sirvent
Audrey
A
GENFIT, Parc Eurasanté, Loos, France.
Verhoeven
Adrie J M
AJ
Jansen
Hans
H
Kosykh
Vladimir
V
Darteil
Raphaël J
RJ
Hum
Dean W
DW
Fruchart
Jean-Charles
JC
Staels
Bart
B
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D020868:Gene Silencing; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008049:Lipase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D008024:Ligands; D008049:Lipase; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D012313:RNA; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C504173:LIPC protein, human