Importance of fatty acid binding proteins in cellular function and organismal metabolism

Abstract

Fatty acid binding proteins (Fabps) are small soluble proteins that are abundant in the cytosol. These proteins are known to bind a myriad of small hydrophobic molecules and have been postulated to serve a variety of roles, yet their precise functions have remained an enigma over half a century of study. Here, we consider recent findings, along with the cumulative findings contributed by many laboratories working on Fabps over the last half century, to synthesize a new outlook for what functions Fabps serve in cells and organisms. Collectively, the findings illustrate that Fabps function as versatile multi-purpose devices serving as sensors, conveyors and modulators to enable cells to detect and handle a specific class of metabolites, and to adjust their metabolic capacity and efficiency.

Keywords: Fabp; gene expression; metabolism; modulator; sensor; transporter.

FIGURE 1

Structures of Fabps from different organisms determined experimentally (A, B) or predicted by AlphaFold (https://alphafold.ebi.ac.uk/) (C–F). (A) Rat Fabp2 with bound ligand, determined by x‐ray crystallography (RCSB PDB 2IFB). (B) Human FABP5, determined by NMR spectroscopy (RCSB PDB 1JJJ). (C) Trichoplax adhaerens FABP domain‐containing protein (AlphaFold entry B3S4H2). (D) Caenorhabditis elegans lbp‐8 (AlphaFold entry O02324). (E) Schistocerca gregaria Fabp structure predicted from nucleotide sequence (NCBI accession XP_049839815.1) using AlphaFold2 via Colaboratory (https://colab.research.google.com/). (F) Danio rerio fabp4a (AlphaFold entry Q66I80).

FIGURE 2

Model of Fabp function. Fabps function as sensors, conveyors and modulators of cellular function. Small hydrophobic molecules (e.g. fatty acids, bile acids) that serve as Fabp ligands (black circle) enter cells via solute transporters (represented in green), or partition into the plasma membrane, are taken up by Fabps (represented in light brown). Each Fabp type has distinct ligand preferences as well as preferred protein binding partners (e.g. represented in orange and cyan in the figure) with different affinities for unliganded and liganded Fabps. Liganded Fabps transport their cargos to their sites of utilization. These include the nucleus (represented in purple) and other organelles (represented in beige). In the nucleus, Fabps interact with a variety of transcription factors (represented in blue), including but not limited to nuclear receptors which accept their cargos, to regulate the expression of their target genes. Fabp ligands conveyed into the nucleus may leave the nucleus via Fabps. In other organelles, both unliganded and liganded Fabps can interact with the cytosolic domains of membrane‐bound transmembrane proteins to modulate their activities (organellar transmembrane proteins represented in orange; plasma membrane transmembrane proteins represented in cyan). Fabp ligands delivered to organelles can be metabolized (e.g. fatty acids converted to triacylglycerols for storage or oxidized for energy). Alternatively, fatty acids released during hydrolysis of triacylglycerols, or other fatty acid esters, can be captured by Fabps and conveyed to other sites of utilization. Fabps may offload their cargos to various membrane systems (plasma and organellar membranes) by desorption, or via membrane‐bound transporters. Cellular export of Fabp ligands can be achieved by interaction of the liganded Fabp with plasma membrane‐localized solute exporters (e.g. represented in green at the bottom of figure).