Severe atherosclerosis and hypoalphalipoproteinemia in the staggerer mouse, a mutant of the nuclear receptor RORalpha.
BACKGROUND
Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown.


RESULTS
We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORalpha gene, develops severe atherosclerosis when maintained on an atherogenic diet. In addition, sg/sg mice display a profound hypoalphalipoproteinemia, which is associated with decreased plasma levels of the major HDL proteins, apolipoprotein (apo) A-I and apoA-II. This decrease in HDL levels in sg/sg mice is due to lowered apoA-I gene expression in the intestine but not in the liver. ApoA-II gene expression is unaffected.


CONCLUSIONS
These results suggest that the RORalpha gene contributes to the plasma HDL level and susceptibility to atherosclerosis.
Mamontova
A
A
INSERM U141 and IFR "Circulation Lariboisière," Rhône-Poulenc Rorer, Gencell Division, Atherosclerosis Department, Centre de recherches de Vitry-Alfortville, France.
Séguret-Macé
S
S
Esposito
B
B
Chaniale
C
C
Bouly
M
M
Delhaye-Bouchaud
N
N
Luc
G
G
Staels
B
B
Duverger
N
N
Mariani
J
J
Tedgui
A
A
D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016633:Apolipoprotein A-II / Q000097:blood / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004036:Diet, Atherogenic; D005260:Female; D017353:Gene Deletion; D007413:Intestinal Mucosa / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood* / Q000172:deficiency*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000235:genetics; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D009419:Nerve Tissue Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D002784:Cholesterol