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High density lipoprotein (HDL) binds to cell surface receptors and promotes selective removal of excess cholesterol from intracellular pools. The activity of this receptor is up-regulated when cells become loaded with cholesterol, but the relative degree of up-regulation depends on the growth state of the cells. The current study demonstrates that treatment of proliferating fibroblasts with gamma-interferon (IFN) increases the activity of the HDL receptor in association with a decrease in the rate of cell proliferation. Addition of IFN during the growth phase reduced the number of cells but had little effect on total cell protein, indicating that IFN inhibited cell proliferation but produced larger cells. IFN treatment increased the number of high affinity receptors for HDL on the surface of cholesterol-loaded fibroblasts, whether receptor binding was expressed per cell or per unit of cell surface area, cell protein, or cell cholesterol. IFN treatment also appeared to increase the amount of 110-kDa HDL binding protein in fibroblast membranes that has been postulated to represent the HDL receptor molecule. The IFN-induced increase in HDL receptor activity was associated with an enhanced ability of HDL3 to remove cholesterol from intracellular pools. These results are consistent with the hypothesis that inhibition of cell proliferation increases HDL receptor-mediated transport of excess cholesterol from cells, possibly to rid cells of cholesterol that accumulates in response to a reduced rate of membrane synthesis.

High-density lipoprotein (HDL3) particles bind to a cell surface receptor, thereby promoting the efflux of cholesterol from extrahepatic nonsteroidogenic cells. This receptor appears to be upregulated by increased cell cholesterol content and also may be responsive to the growth state of cells. Because insulin can be mitogenic, the effect of insulin on HDL-receptor function was tested. HDL-receptor activity of cholesterol-loaded fibroblasts was inhibited by insulin treatment. Insulin decreased HDL binding in a log-dose fashion (-25% at 67 nM insulin) in association with increases in [3H]thymidine incorporation into DNA. HDL-mediated cholesterol efflux from cholesterol-loaded cells was diminished by insulin treatment of cells in parallel with decreased HDL binding. Insulin induced reciprocal changes in HDL- and low-density lipoprotein (LDL)-receptor activity. In cells in which these receptors were upregulated by varying cell cholesterol content, insulin increased LDL binding (+88%) and decreased HDL binding (-24%). Insulin-like growth factor I (IGF-I, 100 ng/ml) also significantly decreased HDL binding and HDL-mediated cholesterol efflux to a comparable degree. Pooled human serum similarly induced a reduction in HDL binding to its receptor. These results are consistent with the hypothesis that growth factors in general, and insulin and IGF-I in particular, decrease HDL-receptor activity, possibly to promote retention of cholesterol needed for new membrane synthesis during cell proliferation. Such a mechanism could be partly responsible for accumulation of cholesteryl esters in arterial wall cells during atherogenesis in diabetes mellitus.

High density lipoprotein (HDL) receptor activity was decreased by the addition of platelet-derived growth factor (PDGF) to cholesterol-loaded cultured human skin fibroblasts. Effects were observed within 12 hours, coinciding with increases in tritiated thymidine incorporation into DNA. The PDGF-mediated decrease in HDL binding was associated with a decrease in cholesterol efflux promoted by HDL3. PDGF exerted reciprocal effects on HDL and low density lipoprotein (LDL) receptor activity. With fibroblasts not loaded with cholesterol, PDGF increased LDL binding without changing HDL receptor activity. With cholesterol-loaded cells, PDGF decreased HDL receptor activity without changing LDL receptor activity. These results show that a reduction in HDL receptor activity is an additional cellular response to PDGF. Decreased HDL-mediated cholesterol efflux may result in retention of cholesterol needed for membrane synthesis in cells stimulated to proliferate.