Identification of Rev-erbalpha as a physiological repressor of apoC-III gene transcription.
Elevated serum levels of triglyceride-rich remnant lipoproteins (TRL) are a major risk factor predisposing a subject to atherosclerosis. Apolipoprotein C-III (apoC-III) is a major constituent of TRL that impedes triglyceride hydrolysis and remnant clearance and, as such, may exert pro-atherogenic activities. In the present study, transient cotransfection experiments in rat hepatocytes in primary culture and rabbit kidney RK13 cells demonstrated that overexpression of Rev-erbalpha specifically decreases basal and HNF-4 stimulated human apoC-III promoter activity. A Rev-erbalpha response element was mapped by promoter deletion, mutation analysis, and gel-shift experiments to a AGGTCA half-site located at position -23/-18 (downstream of the TATA box) in the apoC-III promoter. Finally, Rev-erbalpha-deficient mice displayed elevated serum and liver mRNA levels of apoC-III together with increased serum VLDL triglycerides. Taken together, our data identify Rev-erbalpha as a regulator of apoC-III gene expression, providing a novel, physiological role for this nuclear receptor in the regulation of lipid metabolism.
Raspé
Eric
E
UR 545 INSERM, Institut Pasteur de Lille, 1 rue Calmette, 59019 Lille, France.
Duez
Hélène
H
Mansén
Anethe
A
Fontaine
Coralie
C
Fiévet
Catherine
C
Fruchart
Jean-Charles
JC
Vennström
Bjorn
B
Staels
Bart
B
D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000097:blood / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D022781:Hepatocytes; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D015243:Cholesterol, VLDL; D004268:DNA-Binding Proteins; C064353:NR1D1 protein, human; C498262:Nr1d1 protein, mouse; C498263:Nr1d1 protein, rat; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear