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

Atherosclerosis. 2001 Jan;154(1):103-12. doi: 10.1016/s0021-9150(00)00471-8.

Abstract

Apolipoprotein E (apoE) is a high affinity ligand for several receptor systems in the liver, including the low-density lipoprotein (LDL) receptor, and non-LDL receptor sites, like the LDL receptor-related protein (LRP), the putative remnant receptor and/or proteoglycans. Although the liver is the major source of apoE synthesis, apoE is also produced by a wide variety of other cell types, including macrophages. In the present study, the role of the LDL receptor in the removal of lipoprotein remnants, enriched with macrophage-derived apoE from the circulation, was determined using the technique of bone marrow transplantation (BMT). Reconstitution of macrophage apoE production in apoE-deficient mice resulted in a serum apoE concentration of only 2% of the concentration in wild-type C57Bl/6 mice. This low level of apoE nevertheless reduced VLDL and LDL cholesterol 12-fold (P<0.001) and fourfold (P<0.001), respectively, thereby reducing serum cholesterol levels and the susceptibility to atherosclerosis. In contrast, reconstitution of macrophage apoE synthesis in mice lacking both apoE and the LDL receptor induced only a twofold (P<0.001) reduction in VLDL cholesterol and had no significant 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 removal 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / pathology
  • Apolipoproteins E / biosynthesis
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Apolipoproteins E / physiology*
  • Arteriosclerosis / pathology
  • Arteriosclerosis / prevention & control*
  • Bone Marrow / metabolism
  • Bone Marrow Transplantation
  • Cholesterol / blood*
  • Liver / metabolism*
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout / genetics
  • Receptors, LDL / genetics
  • Receptors, LDL / physiology*

Substances

  • Apolipoproteins E
  • Receptors, LDL
  • Cholesterol