Abstract

Independently of its role in lipid homeostasis, apolipoprotein E (apoE) inhibits cell proliferation. We compared the effects of apoE added to media (exogenous apoE) with the effects of stably expressed apoE (endogenous apoE) on cell proliferation. Exogenous and endogenous apoE increased population doubling times by 30-50% over a period of 14 days by prolonging the G(1) phase of the cell cycle. Exogenous and endogenous apoE also decreased serum-stimulated DNA synthesis by 30-50%. However, apoE did not cause cell cycle arrest; both apoE-treated and control cells achieved equivalent saturation densities at 14 days. Further analyses demonstrated that exogenous and endogenous apoE prevented activation of MAPK but not induction of c-fos expression in response to serum growth factors. Endogenous (but not exogenous) apoE altered serum concentration-dependent effects on proliferation. Whereas control (non-apoE-expressing) cell numbers increased with increasing serum concentrations (1.6-fold for every 2-fold increase in serum), apoE-expressing cell numbers did not differ as serum levels were raised from 2.5 to 10%. In addition, in low serum (0.1%), apoE-expressing cells had elevated DNA synthesis levels compared with control cells. We conclude that apoE does not simply inhibit cell proliferation; rather, the presence of apoE alters the response to and requirement for serum mitogens.

Highlights

  • Apolipoprotein E1 plays an important role in the progression of atherosclerosis [1], and different isoforms are associated with varying risks of Alzheimer’s disease [2]

  • ApoE can reach cells from two sources: exogenous apolipoprotein E (apoE), usually as a component of lipoproteins, or endogenous apoE

  • Isolation of ApoE-expressing Cell Lines—To compare the effects of exogenous apoE added to cells via the culture medium with the effects of endogenous apoE, we established stably transfected derivatives of the rat F111 embryonic fibroblast cell line

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Summary

ApoE and Cell Proliferation

Stably expressed apoE in a rat fibroblast cell line (F111 cells) that normally does not express apoE. The proliferation properties of parental F111 cells have been previously characterized in detail (19 –21). Cells expressing the apoE transgene were defined as Eϩ cells, in contrast to EϪ cells carrying only the control plasmid (encoding hygromycin resistance). Responses of cells to serum were determined in the presence or absence of exogenous apoE. Our results indicate that exogenous apoE and endogenous apoE exhibit similar effects on cell proliferation at a fixed serum concentration, cell proliferative responses to apoE differ dramatically under serum-deprived versus serum-stimulated conditions

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