Lack of macrophage fatty-acid–binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis

Abstract

The adipocyte fatty-acid-binding protein, aP2, has an important role in regulating systemic insulin resistance and lipid metabolism. Here we demonstrate that aP2 is also expressed in macrophages, has a significant role in their biological responses and contributes to the development of atherosclerosis. Apolipoprotein E (ApoE)-deficient mice also deficient for aP2 showed protection from atherosclerosis in the absence of significant differences in serum lipids or insulin sensitivity. aP2-deficient macrophages showed alterations in inflammatory cytokine production and a reduced ability to accumulate cholesterol esters when exposed to modified lipoproteins. Apoe-/- mice with Ap2+/+ adipocytes and Ap2-/- macrophages generated by bone-marrow transplantation showed a comparable reduction in atherosclerotic lesions to those with total aP2 deficiency, indicating an independent role for macrophage aP2 in atherogenesis. Through its distinct actions in adipocytes and macrophages, aP2 provides a link between features of the metabolic syndrome and could be a new therapeutic target for the prevention of atherosclerosis.

Lipid signalling in disease

“…Another important group of molecules that coordinates lipid responses in adipocytes includes lipid chaperone proteins, such as fatty acid binding proteins (FABPs). Animals that lack FABP4 and FABP5 exhibit a fatty acid-resistant phenotype similar to that of mice and humans that are given PPAR ligands, indicating that FABPs and PPARs might function in similar pathways to control the biological effects of lipids 50,51 . Remarkably, mice lacking FABP4 or FABP5, or animals treated with a small-molecule inhibitor of FABP4, are protected against almost every aspect of the metabolic syndrome, including visceral obesity, insulin resistance, hepatosteatosis and atherosclerosis 50,52-54 .…”

“…Targeting the hormone-sensitive lipase (HSL), which liberates free fatty acids for cellular uptake, is an option that has been realized with the use of orlistat. Similarly, smallmolecule inhibitors of FABP4 have produced promising results in preventing metabolic syndrome in high-fat diet animal models, and raises hopes that this strategy might advance further 50,[52][53][54] . Cellular stress that is caused by an excess of fatty acids can be alleviated using orally active chemical chaperones that act to stabilize protein conformation and improve the protein folding capacity of the ER.…”

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…As in other cells, FAs in macrophages bind to fatty acid-binding proteins that are responsible for their intracellular trafficking. In macrophages, the absence of aP2, a fatty acid-binding protein, protects ApoE-deficient mice against atherosclerosis (Makowski et al, 2001).…”

Mechanisms by which diabetes increases cardiovascular disease

“…aP2 −/− mice are obese but protected against insulin resistance [57]. aP2 deficiency also reduces atherosclerotic lesions in Apoe −/− mice [58]. Recently, pharmacological inhibition of aP2 has been demonstrated to reduce atherosclerosis in Apoe −/− mice, probably due to inhibition of foam cell formation, production of inflammatory chemokines and cytokines [59].…”