Essential role for the (hepatic) LDL receptor in macrophage apolipoproteinE-induced reduction in serum cholesterol levels and atherosclerosis

Apolipoprotein E (apoE) is a high affinity ligand for several receptor syst ems in the liver, including the low-density lipoprotein (LDL) receptor, and non-LDL receptor sites, like the LDL receptor-related protein (LRP), the p utative remnant receptor and/or proteoglycans. Although the liver is the ma jor source of apoE synthesis, apoE is also produced by a wide variety of ot her cell types, including macrophages. in the present study, the role of th e LDL receptor in the removal of lipoprotein remnants, enriched with macrop hage-derived apoE from the circulation, was determined using the technique of bone marrow transplantation (BMT). Reconstitution of macrophage apoE pro duction in apoE-deficient mice resulted in a serum apoE concentration of on ly 2% of the concentration in wild-type C57Bl/6 mice. This low level of apo E nevertheless reduced VLDL and LDL cholesterol 12-fold (P < 0.001) and fou rfold (P < 0.001), respectively, thereby reducing serum cholesterol levels and the susceptibility to atherosclerosis. In contrast, reconstitution of m acrophage apoE synthesis in mice lacking both apoE and the LDL receptor ind uced only a twofold (P < 0.001) reduction in VLDL cholesterol and had no si gnificant effect on atherosclerotic lesion development, although serum apoE levels were 93% of the concentration in normal C57Bl/6 mice. In conclusion , a functional (hepatic) LDL receptor is essential for the efficient remova l of macrophage apoE-enriched lipoprotein remnants from the circulation and thus for normalization of serum cholesterol levels and protection against atherosclerotic lesion development in apoE-deficient mice. (C) 2001 Elsevie r Science Ireland Ltd. All rights reserved.