Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets

Abstract

Fatty acids function both as an energy source and as metabolic signalling molecules and affect many vital processes. This complexity combined with the chemical characteristics of lipids present many challenges in their trafficking, compartmentalization and specific target engagement properties within and between cells. Intracellular lipid chaperones dictate the destiny of lipids. Also known as fatty acid-binding proteins (FABPs), these are a group of proteins that coordinate lipid trafficking and signalling in cells, and some isoforms are also strongly linked to metabolic and inflammatory pathways. At least nine FABPs have been identified to date, which exhibit unique patterns of tissue expression. The family contains liver (L-), intestinal (I-), heart (H-), adipocyte (A-), epidermal (E-), ileal (Il-), brain (B-), myelin (M-) and testis (T-) FABPs. Adipocytes and macrophages jointly express two FABPs: A-FABP (also known as aP2/FABP4) and E-FABP (also known as mal1/FABP5), which are the best-studied FABPs. They play a central role in many aspects of metabolic diseases including obesity, diabetes, fatty liver disease, asthma and atherosclerosis. The loss-of-function genetic models of these isoforms are essentially free of metabolic disease and indicate the therapeutic potential of targeting these proteins in metabolic disease. In fact, humans with a genetic variation causing aP2 haploinsufficiency are resistant against type 2 diabetes and cardiovascular disease. Recently, it has been shown that it is possible to rationally design an orally active, high affinity, potent and selective synthetic inhibitor of A-FABP. Administration of this inhibitor markedly reduced the extent of atherosclerosis and improved insulin sensitivity in distinct genetic and/or dietary models of atherosclerosis and type 2 diabetes.