31 May 2001. 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
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.
Reference: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