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

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.

Figure 1. Putative functions of FABP in the cell

Fatty-acid (FA) trafficking accompanied by the fatty acid-binding proteins (FABPs) in the cell is shown. As lipid chaperones, FABPs have been proposed to play a role in the transport of lipids to specific compartments in the cell: to lipid droplets for storage; to the endoplasmic reticulum for signalling, trafficking and membrane synthesis; to the mitochondria or peroxisome for oxidation; to cytosolic or other enzymes to regulate their activity; to the nucleus for the control of lipid-mediated transcriptional programs via nuclear hormone receptors (NHRs) or other transcription factors that respond to lipids; or even outside the cell to signal in an autocrine or paracrine manner.

Figure 2. Functions of A-FABP in the adipocyte and macrophage

a. Other than general functions of the fatty acid-binding protein (FABP), adipocyte FABP (A-FABP; FABP4) interacts with hormone-sensitive lipase (HSL) to potentially modulate its catalytic activity and integrates several signalling networks that control inflammatory responses potentially through JNK/inhibitor of kappa kinase (IKK) and insulin action in the adipocyte. In addition to regulating fatty-acid influx, A-FABP is also important in controlling adipocyte lipid hormone production to regulate distant targets. The transcriptional events resulting from these actions are not fully understood. b. In the macrophage, A-FABP regulates inflammatory responses via the IKK-nuclear factor-κB (NF-κB) pathway and attenuates cholesterol efflux through inhibition of the peroxisome proliferator-activated receptor-γ (PPAR-γ)-liver X receptor-α (LXR-α)-ATP-binding cassette A1 (ABCA1) pathway. In both macrophages and adipocytes, A-FABP has a critical role in integrating lipid signals to organelle responses, particularly in the endoplasmic reticulum (ER). AP1, adaptor protein 1; IGF, insulin-like growth factor; IRS, insulin receptor substrate; TNF, tumour necrosis factor.

Figure 3. Crystal structure of the synthetic A-FABP inhibitor BMS309403 bound to human A-FABP

Human fatty acid-binding protein (FABP) crystallized in complex with BMS309403, a synthetic adipocyte FABP (A-FABP; FABP4) inhibitor, is shown (PDB code: 2nnq). The molecule occupies the internal binding pocket of A-FABP. One side of the internal surface of the binding pocket is shown as a grey colour where the designed surface interaction with the synthetic inhibitor takes place. The figure was created using PyMOL and provided by R. Parker, Bristol–Myers Squibb.