Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression.
OBJECTIVE
Increased serum triglyceride levels constitute a risk factor for coronary heart disease. Apolipoprotein CIII (Apo CIII) is a determinant of serum triglyceride metabolism. In this study, we investigated whether activators of the nuclear farnesoid X receptor (FXR) modulate Apo CIII gene expression.


METHODS
The influence of bile acids and synthetic FXR activators on Apo CIII and triglyceride metabolism was studied in vivo by using FXR wild-type and FXR-deficient mice and in vitro by using human primary hepatocytes and HepG2 cells.


RESULTS
In mice, treatment with the FXR agonist taurocholic acid strongly decreased serum triglyceride levels, an effect associated with reduced Apo CIII serum and liver messenger RNA levels. By contrast, no change was observed in FXR-deficient mice. Incubation of human primary hepatocytes and HepG2 cells with bile acids or the nonsteroidal synthetic FXR agonist GW4064 resulted in a dose-dependent down-regulation of Apo CIII gene expression. Promoter transfection experiments and mutation analysis showed that bile acid-activated FXR decrease human Apo CIII promoter activity via a negative FXR response element located in the I(4) footprint between nucleotides -739 and -704. Chromatin immunoprecipitation experiments showed that bile acid treatment led to binding of FXR/retinoid X receptor heterodimers to and displacement of HNF4alpha from this site. Bile acid treatment still repressed liver Apo CIII gene expression in hepatic HNF4alpha-deficient mice, suggesting an active rather than a competitive mechanism of Apo CIII repression by the FXR.


CONCLUSIONS
We identified bile acid and synthetic activators of the nuclear FXR as negative regulators of Apo CIII expression, an effect that may contribute to the triglyceride-decreasing action of FXR agonists.
Claudel
Thierry
T
UR545 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille, Lille, France.
Inoue
Yusuke
Y
Barbier
Olivier
O
Duran-Sandoval
Daniel
D
Kosykh
Vladimir
V
Fruchart
Jamila
J
Fruchart
Jean-Charles
JC
Gonzalez
Frank J
FJ
Staels
Bart
B
D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics* / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001647:Bile Acids and Salts / Q000494:pharmacology; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000502:physiology; D002792:Cholestyramine Resin / Q000494:pharmacology; D004268:DNA-Binding Proteins; D019281:Dimerization; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4; D022781:Hepatocytes; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology; D020218:Response Elements; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D002792:Cholestyramine Resin; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; D007555:Isoxazoles; D010750:Phosphoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C496592:HNF4A protein, human; C496593:Hnf4a protein, mouse; C403128:MLX protein, human; C501970:Tcfl4 protein, mouse; C412815:GW 4064