Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORalpha.
OBJECTIVE
The newly identified apolipoprotein A5 (APOA5), selectively expressed in the liver, is a crucial determinant of plasma triglyceride levels. Because elevated plasma triglyceride concentrations constitute an independent risk factor for cardiovascular diseases, it is important to understand how the expression of this gene is regulated. In the present study, we identified the retinoic acid receptor-related orphan receptor-alpha (RORalpha) as a regulator of human APOA5 gene expression.


RESULTS
Using electromobility shift assays, we first demonstrated that RORalpha1 and RORalpha4 proteins can bind specifically to a direct repeat 1 site present at the position -272/-260 in the APOA5 gene promoter. In addition, using transient cotransfection experiments in HepG2 and HuH7 cells, we demonstrated that both RORalpha1 and RORalpha4 strongly increase APOA5 promoter transcriptional activity in a dose-dependent manner. Finally, adenoviral overexpression of hRORalpha in HepG2 cells led to enhanced hAPOA5 mRNA accumulation. We show that the homologous region in mouse apoa5 promoter is not functional. Moreover, we show that in staggerer mice, apoa5 gene is not affected by RORalpha.


CONCLUSIONS
These findings identify RORalpha1 and RORalpha4 as transcriptional activators of human APOA5 gene expression. These data suggest an additional important physiological role for RORalpha in the regulation of genes involved in lipid homeostasis and probably in the development of atherosclerosis.
Genoux
Annelise
A
Département d'Athérosclérose, U.545 INSERM, Institut Pasteur de Lille and Faculté de Pharmacie de Lille, Lille Cedex, France.
Dehondt
Hélène
H
Helleboid-Chapman
Audrey
A
Duhem
Christian
C
Hum
Dean W
DW
Martin
Geneviève
G
Pennacchio
Len A
LA
Staels
Bart
B
Fruchart-Najib
Jamila
J
Fruchart
Jean-Charles
JC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000235:genetics*; D001054:Apolipoproteins A; D050197:Atherosclerosis / Q000235:genetics / Q000503:physiopathology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; C539738:RORA protein, human; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014280:Triglycerides; C078716:ROR1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors