A recycling pathway for resecretion of internalized apolipoprotein E in liver cells

We have investigated the recycling of apoE in livers of apoE(-/-) mice tran splanted with wild type bone marrow (apoE(+/+) --> apoE(-/-)), a model in w hich circulating apoE is derived exclusively from macrophages. Nascent Gels lipoproteins were recovered from livers of apoE(+/+) --> apoE(-/-) mice 8 weeks after transplantation. ApoE was identified with nascent d < 1.006 and with d 1.006-1.210 g/ml lipoproteins at a level similar to6% that of nasce nt lipoproteins from C57BL/6 mice. Hepatocytes from apoE(+/+) --> apoE(-/-) mice were isolated and cultured in media free of exogenous apoE, ApoE was found in the media primarily on the d < 1.006 g/ml fraction, indicating a r esecretion of internalized apoprotein. Secretion of apoE from C57BL/6 hepat ocytes was consistent with constitutive production, whereas the majority of apoE secreted from apoE(+/+) --> apoE(-/-) hepatocytes was recovered in th e last 24 h of culture, This suggests that release may be triggered by accu mulation of an acceptor, such as very low density lipoproteins, in the medi a. In agreement with the in vivo data, total recovery of apoE from apoE(+/) --> apoE(-/-) hepatocytes was similar to6% that of the apoE recovered fro m C57BL/6 hepatocytes. Since plasma apoE levels in the transplanted mice ar e similar to 10% of control levels, the findings indicate that up to 60% of the internalized apoE may be reutilized under physiologic conditions. Thes e studies provide definitive evidence for the sparing of apoE and its routi ng through the secretory pathway and demonstrate that internalized apoE can be resecreted in a quantitatively significant fashion.