© 1997 American Heart Association, Inc.
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Human Leukemia Inhibitory Factor Upregulates LDL Receptors on Liver Cells and Decreases Serum Cholesterol in the Cholesterol-Fed Rabbit
From the Centre for Research in Vascular Biology, Department of Anatomical Sciences, The University of Queensland, Brisbane, Australia.
Correspondence to Professor Julie H. Campbell, Centre for Research in Vascular Biology, Department of Anatomical Sciences, The University of Queensland, Brisbane QLD 4072, Australia. E-mail julie.campbell{at}mailbox.uq.oz.au
Abstract In a previous study, we found that the
cytokine (human) leukemia inhibitory factor (hLIF)
significantly reduced plasma cholesterol levels and the
accumulation of lipid in aortic tissues of cholesterol-fed
rabbits after 4 weeks of treatment. The mechanisms by which this occurs
were investigated in the present study. This involved examining the
effect of hLIF on (1) the level of plasma cholesterol at
different times throughout the 4-week treatment and diet period; (2)
smooth muscle cell (SMC) and macrophage-derived foam cell
formation in vitro; and (3) LDL receptor expression and uptake in the
human hepatoma cell line HepG2. At time zero, an osmotic minipump (2-mL
capacity; infusion rate, 2.5 µL/h; 28 days) containing either hLIF
(30 µg · kg-1 · d-1) or
saline was inserted into the peritoneal cavity of New Zealand White
rabbits (N=24). Rabbits were divided into four groups of six animals
each. Group 1 received a normal diet/saline; group 2, a normal
diet/hLIF; group 3, a 1% cholesterol diet/saline; and
group 4, a 1% cholesterol diet/hLIF. hLIF had no effect on
the plasma lipids or artery wall of group 2 rabbits (normal diet).
However, in group 4 rabbits, plasma cholesterol levels and
the percent surface area of thoracic aorta covered by fatty streaks was
decreased by 
30% and 80%, respectively, throughout all stages of
the 4-week treatment period. In vitro, hLIF failed to prevent
lipoprotein uptake by either SMCs or macrophages (foam cell
formation) when the cells were exposed to ß-VLDL for 24 hours. In
contrast, hLIF (100 ng/mL) added to cultured human hepatoma HepG2 cells
induced a twofold or threefold increase in intracellular lipid
accumulation in the medium containing 10% lipoprotein-deficient serum
or 10% fetal calf serum, respectively. This was accompanied by a
significant non–dose-dependent increase in LDL receptor expression in
hLIF-treated HepG2 cells incubated with LDL (20 µg/mL) when compared
with controls (P<.05) incubated in control medium alone
(P<.05). We suggest that the hLIF-induced lowering of
plasma cholesterol and tissue cholesterol
levels (inhibition of fatty streak formation) in the
hyperlipidemic rabbit is due in part to upregulation of
hepatic LDL receptors, with resultant increased clearance of
lipoprotein-associated cholesterol from the circulation.
There is an additional and as-yet-unknown mechanism acting at the level
of the vessel wall that appears to be affecting the process of
arterial cholesterol accumulation.
Key Words: leukemia inhibitory factor • cholesterol • LDL • hepatocytes • rabbits
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