HUMAN LEUKEMIA INHIBITORY FACTOR UP-REGULATES LDL RECEPTORS ON LIVER-CELLS AND DECREASES SERUM-CHOLESTEROL IN THE CHOLESTEROL-FED RABBIT

In a previous study, we found that the cytokine (human) leukemia inhib itory factor (hLIF) significantly reduced plasma cholesterol levels an d the accumulation of lipid in aortic tissues of cholesterol-fed rabbi ts after 4 weeks of treatment. The mechanisms by which this occurs wer e investigated in the present study. This involved examining the effec t of hLIF on (1) the level of plasma cholesterol at different times th roughout 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 mu L/h; 28 days) containing either hLIF (30 mu g.kg(-1).d(-1)) or sali ne was inserted into the peritoneal cavity of New Zealand White rabbit s (N=24). Rabbits were divided into four groups of six animals each. G roup 1 received a normal diet/saline; group 2, a normal diet/hLIF; gro up 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 choleste rol levels and the percent surface area of thoracic aorta covered by f atty streaks was decreased by approximate to 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 (f oam cell formation) when the cells were exposed to P-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 signi ficant non-dose-dependent increase in LDL receptor expression in hLIF- treated HepG2 cells incubated with LDL (20 mu g/mL) when compared with controls (P<.05) incubated in control medium alone (P<.05). We sugges t that the hLIF-induced lowering of plasma cholesterol and tissue chol esterol levels (inhibition of fatty streak formation) in the hyperlipi demic rabbit is due in part to upregulation of hepatic LDL receptors, with resultant increased clearance of lipoprotein-associated cholester ol from the circulation. There is an additional and as-yet-unknown mec hanism acting at the level of the vessel wall that appears to be affec ting the process of arterial cholesterol accumulation.