POTENT CHOLESTEROL-LOWERING EFFECT BY HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN RABBITS - POSSIBLE IMPLICATIONS OF ENHANCEMENT OF MACROPHAGE FUNCTIONS AND AN INCREASE IN MESSENGER-RNA FOR VLDL RECEPTOR

The mechanism by which granulocyte-macrophage colony-stimulating facto r (GM-CSF) lowers plasma cholesterol levels is not well understood. We tested recombinant human GM-CSF (rhGM-CSF) on plasma cholesterol and triglycerides in rabbits and attempted to determine the mechanisms of the cholesterol-lowering effect. rhGM-CSF (20 mu g.kg(-1).d(-1)) was a dministered to normal and cholesterol-fed rabbits for 2 weeks and to W atanabe heritable hyperlipidemic (WHHL) rabbits for 1 week. The admini stration of rhGM-CSF markedly lowered cholesterol and triglycerides, a n effect that persisted in normal and cholesterol-fed rabbits even aft er termination of treatment. The cholesterol-lowering effect of rhGM-C SF was also observed in WHHL rabbits. rhGM-CSF was capable of stimulat ing granulocyte-macrophage colony formation in vitro in rabbits with a n effect comparable to that in humans. Northern blot analysis with rab bit very-low-density-lipoprotein (VLDL) receptor cDNA revealed that rh GM-CSF increased the levels of VLDL receptor mRNA in muscle of rabbits after only 1.5 hours of treatment compared with control (2.6-fold), w ith the 1.5-fold increase following a 5-day administration. No changes in the levels of LDL receptor mRNA in liver, spleen, and bone marrow were observed in the treated rabbits. These findings suggest that the cholesterol-lowering effect of rhGM-CSF may be mediated by enhancement of macrophage functions in lipid metabolism and the increase in mRNA for VLDL receptor in rabbits.