The Multifunctional Family of Mammalian Fatty Acid–Binding Proteins

Abstract

Fatty acid–binding proteins (FABPs) are small lipid-binding proteins abundantly expressed in tissues that are highly active in fatty acid (FA) metabolism. Ten mammalian FABPs have been identified, with tissue-specific expression patterns and highly conserved tertiary structures. FABPs were initially studied as intracellular FA transport proteins. Further investigation has demonstrated their participation in lipid metabolism, both directly and via regulation of gene expression, and in signaling within their cells of expression. There is also evidence that they may be secreted and have functional impact via the circulation. It has also been shown that the FABP ligand binding repertoire extends beyond long-chain FAs and that their functional properties also involve participation in systemic metabolism. This article reviews the present understanding of FABP functions and their apparent roles in disease, particularly metabolic and inflammation-related disorders and cancers. Expected final online publication date for the Annual Review of Nutrition, Volume 43 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Recent Advances on Small-Molecule Inhibitors of Lipocalin-like Proteins

“…FABPs contain approximately 126–134 amino acids and are approximately 14–15 kDa in molecular weight. FABPs mainly bind fatty acids as ligands, and one FABP molecule usually binds one ligand (except for FABP1 and 6 with two ligands per protein) . The β-barrel of the lipocalin domain differs slightly from that of RBPs and LCNs, with ten β-strands connected by loops and is capped with a αI helix-turn-αII helix lid.…”

“…Almost all FABPs are intracellular proteins that transport ligands between subcellular compartmentations to exert multiple biological functions and participate in the pathogenesis of disease that include metabolic disorders (e.g., diabetes, obesity, and nonalcoholic steatohepatitis), − inflammatory disease (e.g., atherosclerosis and multiple sclerosis), , and cancers in multiple regions …”

“…FABPs mainly bind fatty acids as ligands, and one FABP molecule usually binds one ligand (except for FABP1 and 6 with two ligands per protein). 13 The β-barrel of the lipocalin domain differs slightly from that of RBPs and LCNs, with ten β-strands connected by loops and is capped with a αI helix-turn-αII helix lid. The ten strands are divided into two regions that are vertically orientated to each other in the tertiary structure, forming the ligand-binding βbarrel.…”

“…70−72 Almost all FABPs are intracellular proteins that transport ligands between subcellular compartmentations to exert multiple biological functions and participate in the pathogenesis of disease that include metabolic disorders (e.g., diabetes, obesity, and nonalcoholic steatohepatitis), 73−75 inflammatory disease (e.g., atherosclerosis and multiple sclerosis), 76,77 and cancers in multiple regions. 13 Small-Molecular Inhibitors against FABPs. FABPs exhibit versatile roles in the pathophysiology of various diseases, and some FABP-knockout mice showed a relieved phenotype.…”

“…Due to the structural conservation of lipocalin-like proteins, they share common features such as affinity toward binding to small hydrophobic ligands, forming a transient complex with hydrophilic molecules, and binding receptors at the cell surface. Consequently, they exhibit a wide range of biological functions such as regulating inflammation and immune response as well as cell proliferation, differentiation, and death in addition to nonvesicular lipid trafficking. − Owing to their various biological functions, lipocalin-like proteins play important roles in the pathogenesis of inflammatory, metabolic, and neurological disorders and cancers. − Therefore, these lipocalin-like proteins can serve as potential therapeutic targets of these diseases and small-molecule inhibitors of these proteins are promising in clinical applications.…”