The role of Lipid Chaperones in Integrating Lipid Signals with Inflammatory and Metabolic Responses

Abstract

The mechanistic core of a cluster of diseases associated with obesity appears to reside at the interface of metabolic and inflammatory pathways. Hence, molecules that coordinately control metabolic and inflammatory responses are of great importance for the pathogenesis and therapeutic strategies. We have recently identified two related adipocyte/macrophage fatty acid binding proteins (FABP), aP2 and mal1, as key coordinators of inflammatory and metabolic responses through their integrated actions in adipocytes and macrophages. FABP‐deficiency has a profound impact on lipid homeostasis and provides protection against all pathological components of metabolic syndrome through distinct actions on adipocytes and macrophages. We have reported that macrophage FABPs play a dominant role in atherosclerosis. Recently, we examined the impact of bone marrow‐derived cells in systemic glucose metabolism and demonstrated that FABP action in the stroma is more critical in regulation of systemic insulin sensitivity and hepatosteosis, although bone marrow derived cells also contribute to inflammatory changes in adipose tissue and insulin action. In macrophages, FABPs coordinate lipotoxic responses through a lipid chaperoning mechanisms involving a transcriptional program targeting lipid metabolism. In adipocytes, the principal action of FABPs appears to be through regulation of specific lipid signals that act as endocrine signals at distant sites. Here, I will present these new insights into the mechanism of action of FABPs in different target cells to integrate inflammatory and metabolic pathways and regulate systemic metabolic homeostasis. Finally, the development of an orally active synthetic inhibitor of aP2 and the role of this fatty acid binding protein in human metabolic disease will be discussed.