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

Nature Reviews Drug Discovery volume 7, pages 489–503 (2008)Cite this article

Key Points

  • 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.

Abstract

Lipids are vital components of many biological processes and crucial in the pathogenesis of numerous common diseases, but the specific mechanisms coupling intracellular lipids to biological targets and signalling pathways are not well understood. This is particularly the case for cells burdened with high lipid storage, trafficking and signalling capacity such as adipocytes and macrophages. Here, we discuss the central role of lipid chaperones — the fatty acid-binding proteins (FABPs) — in lipid-mediated biological processes and systemic metabolic homeostasis through the regulation of diverse lipid signals, and highlight their therapeutic significance. Pharmacological agents that modify FABP function may provide tissue-specific or cell-type-specific control of lipid signalling pathways, inflammatory responses and metabolic regulation, potentially providing a new class of drugs for diseases such as obesity, diabetes and atherosclerosis.

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Figure 1: Putative functions of FABP in the cell.
Figure 2: Functions of A-FABP in the adipocyte and macrophage.
Figure 3: Crystal structure of the synthetic A-FABP inhibitor BMS309403 bound to human A-FABP.

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Acknowledgements

Studies on FABPs and related areas in the Hotamisligil laboratory are supported by the National Institutes of Health, USA, and the American Diabetes Association. M.F. has been supported by fellowships from the Japan Society for the Promotion of Science and the American Diabetes Association. We would like to acknowledge the invaluable contributions made by past and current laboratory members and long-standing collaborations, particularly with M. Linton and R. Parker. We also regret the inadvertent omission of many important references owing to space limitations.

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  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, 02115, Massachusetts, USA

    Masato Furuhashi & Gökhan S. Hotamisligil

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  1. Masato Furuhashi
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  2. Gökhan S. Hotamisligil
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Correspondence to Gökhan S. Hotamisligil.

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DATABASES

OMIM

Down's syndrome

obesity

type 2 diabetes

schizophrenia

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Protein Data Bank (PDB)

PyMOL

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Furuhashi, M., Hotamisligil, G. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7, 489–503 (2008). https://doi.org/10.1038/nrd2589

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