Potent cholesterol-lowering effect by human granulocyte-macrophage colony-stimulating factor in rabbits. Possible implications of enhancement of macrophage functions and an increase in mRNA for VLDL receptor.
The mechanism by which granulocyte-macrophage colony-stimulating factor (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 micrograms.kg-1.d-1) was administered to normal and cholesterol-fed rabbits for 2 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for 1 week. The administration of rhGM-CSF markedly lowered cholesterol and triglycerides, an effect that persisted in normal and cholesterol-fed rabbits even after termination of treatment. The cholesterol-lowering effect of rhGM-CSF was also observed in WHHL rabbits. rhGM-CSF was capable of stimulating granulocyte-macrophage colony formation in vitro in rabbits with an effect comparable to that in humans. Northern blot analysis with rabbit very-low-density-lipoprotein (VLDL) receptor cDNA revealed that rhGM-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), with 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.
Ishibashi
T
T
First Department of Internal Medicine, Fukushima Medical College, Japan.
Yokoyama
K
K
Shindo
J
J
Hamazaki
Y
Y
Endo
Y
Y
Sato
T
T
Takahashi
S
S
Kawarabayasi
Y
Y
Shiomi
M
M
Yamamoto
T
T
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism*; D011817:Rabbits; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*; D011994:Recombinant Proteins
D000924:Anticholesteremic Agents; D008055:Lipids; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011973:Receptors, LDL; D011994:Recombinant Proteins; C036053:VLDL receptor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor