Metabolic functions of FABPs--mechanisms and therapeutic implications

Abstract

Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were originally described as intracellular proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for immunometabolic diseases. In particular, genetic deficiency and small molecule-mediated inhibition of FABP4 (also known as aP2) and FABP5 can potently improve glucose homeostasis and reduce atherosclerosis in mouse models. Further research has shown that in addition to their intracellular roles, some FABPs are found outside the cells, and FABP4 undergoes regulated, vesicular secretion. The circulating form of FABP4 has crucial hormonal functions in systemic metabolism. In this Review we discuss the roles and regulation of both intracellular and extracellular FABP actions, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases.

Figure 1

Ribbon and domain structure of FABP4. The structure of FABP4 is depicted as a ribbon with bound oleic acid in space-filling spheres (carboxylate oxygen atoms in red). Also shown are four domains of FABP4: portal region for ligand entry and exit; charge quartet used for protein–protein interactions (Asp17, Asp18, Lys21 and Arg30); the salt bridge where the fatty acid carboxylate forms ion pairs with basic residues within the cavity (Arg106, Arg126 and Tyr128); the hinge where the helix-turn-helix region rotates to enable access of ligands to the cavity (Glu14, Asn15 and Phe16). Amino acid numbering system is based on the mouse Fabp4 protein (Genbank: CAJ18597.1).

Figure 2

Summary of FABP4 intracellular functions. In studies using cultured cells and mouse models, FABP4 carries out a number of intracellular roles. FABP4 suppresses adipose tissue lipogenesis and promotes lipolysis, with direct effects on the composition of the local and circulating free fatty acid pool. FABP4 is also implicated in modulating eicosanoid balance by affecting both COX2 activity and LTA₄ stability, and upregulates UCP2; all these processes influence macrophage function and adipose tissue inflammation. FABPs might mediate PPAR activity by regulating ligand availability, and genetic models suggest that FABP4 opposes PPARγ action. FABP4 can also interact with HSL, JAK2 and CD36. Consequently, FABP4 acts on multiple integrated pathways to regulate lipid metabolism and inflammation, impair insulin action, promote glucose production, and contribute to the pathogenesis of immunometabolic diseases such as diabetes mellitus and atherosclerosis. Abbreviations: COX2, cyclooxygenase 2; ER, endoplasmic reticulum; FABP4, fatty acid binding protein 4; HSL, hormone-sensitive lipase; JAK2, janus kinase 2; JNK, c-jun N-terminal kinase; LTA₄, leukotriene A₄; LXR, liver X receptor; PGE₂, prostaglandin E₂; PPAR, peroxisome proliferator-activated receptor; STAT3, signal transducer and activator of transcription 3; UCP2, uncoupling protein 2.

Figure 3

The association of circulating levels of FABP4 with different human diseases. A summary of studies in humans showing the association of different immunometabolic diseases with circulating levels of FABP4 organized by number of patients. Numbers in the outer circle represent the number of studies in each category. For full list of references included in this figure please see reference list in Supplementary file 1 online. Abbreviations: FABP4, fatty acid binding protein 4; NAFLD, nonalcoholic fatty-liver disease.

Figure 4

Pleiotropic functions of circulating FABP4. FABP4 secretion from adipose tissue is enhanced in the setting of obesity and insulin resistance. The circulating form of FABP4 can function as a hormone and regulate hepatic glucose production. This form of the protein, and lipids regulated by FABP4 such as palmitoleate, also affect insulin action, hepatic lipid metabolism, and cardiac function. Other potential roles of circulating FABP4 include regulation of tumour growth, immune cell functions, endothelial migration, cardiomyocyte contraction and insulin secretion. Abbreviations: FABP4, fatty acid binding protein 4; FFA, free fatty acid. Modified with permission from Elsevier © Cao, H. et al. Adipocyte lipid chaperone aP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 17, 768–778 (2013).

Figure 5

Regulated vesicular secretion of FABP4. The secretion of FABP4 from adipocytes has been demonstrated in vivo in response to fasting and signals that induce lipolysis such as β-AR stimulation. Furthermore, the actions of lipolytic enzymes ATGL and HSL (but not MAGL) are required for the induction of FABP4 secretion, and an influx in FFAs is also sufficient for increased secretion. Following lipolytic stimulation, FABP4 is recruited to multivesicular bodies, and secreted in vesicles that have exosome markers including CD36, calveolin, lactadherin (also known as milk fat globule factor 8 protein), TSG101, and ALIX, as shown on the right. The secretion of FABP4 has also been shown to be responsive to Ca²⁺ signalling, and to be inhibited by insulin. Whether alternative paths exist that support FABP4 secretion is currently unknown. Visualization of multivesicular bodies containing labelled FABP4 (arrows) before and after β-AR stimulation are shown in insets. Abbreviations: β-AR, β-adrenergic receptor; ALIX, programmed cell death 6 interacting protein; ATGL, adipose triglyceride lipase; DAG, diacyl glycerol; FFA, free fatty acid; HSL, hormone-sensitive lipase; MAG, monoacylglycerol; MAGL, monoacylglycerol lipase; MVB, multivesicular body; PKA, protein kinase A; TSG101, tumour susceptibility gene 101 protein.