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
T. Ishibashi et al., 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, Arteriosclerosis and thrombosis, 14(10), 1994, pp. 1534-1541
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.