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

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.

• Authors: M Van Eck, K W Van Dijk, N Herijgers, M H Hofker, P H Groot, T J Van Berkel
• Journal: Atherosclerosis (Atherosclerosis) Vol. 154 Issue 1 Pg. 103-12 (Jan 2001) ISSN: 0021-9150 [Print] Ireland
• PMID: 11137088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Receptors, LDL
• Cholesterol

Topics

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