We investigated the mechanism by which granulocyte-macrophage colony-stimulating factor (GM-CSF) lowers plasma cholesterol levels. Recombinant human GM-CSF (rhGM-CSF) was administered to normal and Watanabe heritable hyperlipidemic (WHHL) rabbits. Treatment with rhGM-CSF reduced the levels of cholesterol and triglyceride in these animals. In vitro colony assay for hematopoietic progenitors indicated that rhGM-CSF was capable of supporting granulocyte-macrophage colony formation in rabbits, suggesting that rhGM-CSF stimulates macrophage function even in rabbits. Northern blot analysis of rabbit very-low density lipoprotein (VLDL) receptor showed that rhGM-CSF elevated the levels of VLDL receptor mRNA 2.6- and 1.8-fold in muscles of normal WHHL rabbits, respectively, 1.5 hours after a single injection. Increases of 1.5- and 1.4-fold were observed in muscles of these rabbits after 5 days of administration. No changes were found in the LDL receptor mRNA levels in liver, spleen or bone marrow. These findings show that the lowering of lipids by GM-CSF may be mediated through the up-regulation of the VLDL receptor mRNA and the enhancement of macrophage function.