Obesity and its frequent cousin, insulin-resistant diabetes, so clearly increase the risk for atherosclerosis that the whole disease complex has been called metabolic syndrome. The underlying mechanisms for this unhappy connection remain poorly understood, however. In the June Nature Medicine, Gokhan Hotamisligil of the Harvard School of Public Health and colleagues elsewhere describe a novel pathway in macrophages that links these problems together and might prove relevant to neurodegeneration, as well.

AP2 is a cytosolic fatty-acid binding protein previously thought to be expressed exclusively in fat cells, where it regulates glucose and lipid metabolism and contributes to insulin resistance in obesity. This paper shows that aP2 is present also in activated macrophages, where it mediates their ability to express the inflammatory cytokines TNF-α, Il-1β, and Il-6, and to store oxidized lipid byproducts.

ApoE-knockout mice-which develop spontaneous hypercholesterolemia and atherosclerosis after about four months and neurodegeneration after eight months-crossed with aP2-knockout mice had up to 87 percent smaller atherosclerotic lesions than did mice lacking only ApoE. To distinguish between the effects of aP2 in fat cells and in macrophages, the scientists irradiated ApoE-negative mice and transplanted backbone marrow with either wildtype or aP2-negative macrophages. Mice lacking aP2 only in their macrophages had 49 percent smaller lesions than did the controls, demonstrating a role for a macrophage aP2 in atherosclerosis in vivo. Finally, the scientists showed that aP2 expression is regulated similarly in macrophages and in fat cells.

Together, these results suggest a potential mechanism underlying metabolic syndrome, the authors write. In this model, yet unknown disease stimuli could modulate in a coordinated way the metabolic status of fat cells (giving rise to insulin resistance in obesity), and the metabolic and inflammatory status of macrophages (promoting atherosclerosis), through pathways that are common to both cell types.

This work is surprising in that it fingered a protein known from lipid metabolism as a regulator of macrophage-mediated inflammation. This raises the question of whether the macrophage component in neurodegeneration also involves aP2 and through this link could reflect an earlier metabolic problem, says Hotamisligil. aP2 appears in microglia, he adds, especially when they are activated. This is intriguing for AD, since the absence of aP2 dramatically reverses ApoE-induced pathology. "Our primary interest now is in the CNS," says Hotamisligil.

aP2 so far appears to have no function in healthy animals, a plus for a potential therapeutic target. It counts among the so-called liability genes thought to have evolved to improve energy efficiency at a time when humans did not live long enough to face problems like type-2 diabetes and Alzheimer's disease.-Gabrielle Strobel.
References: Makowski L, Boord JB, Maeda K, Babaev VR, Uysal KT, Morgan MA, Parker RA, Suttles J, Fazio S, Hotamisligil GS, Linton MF. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001 Jun;7(6):699-705. Abstract

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

No Available Comments

Comments on Primary Papers for this Article

No Available Comments on Primary Papers for this Article

References

Paper Citations

  1. . Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001 Jun;7(6):699-705. PubMed.

Further Reading

Papers

  1. . Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001 Jun;7(6):699-705. PubMed.

Primary Papers

  1. . Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. Nat Med. 2001 Jun;7(6):699-705. PubMed.