Background—Hypoalphalipoproteinemia is the most common lipoprotein abnormality in patients with coronary artery disease, yet its causes are unknown.

Methods and Results—We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORα 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 RORα gene contributes to the plasma HDL level and susceptibility to atherosclerosis.