Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors

Abstract

Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids’ synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…Thus, a wide range of metabolites and agents can activate PPARs during the development of inflammatory response, but their effect on each of the isoforms is very specific. The association between PPAR isoforms and lipid metabolism as well as their high affinity for PUFAs, endocannabinoids, and eicosanoids, has been established [156]. Moreover, PUFAs are precursors for the formation of endogenous specialized proresolving lipid mediators (RvE1, PD1, and LXA4), which are highly active PPARγ agonists.…”

Transcriptome Analysis Reveals Mechanism Underlying the Differential Intestinal Functionality of Laying Hens in the Late Phase and Peak Phase of Production

“…FABP multigene can code for diversified kinds of FABPs such as liver-type FABP (encoded by FABP1), intestinal-type FABP (encoded by FABP2), heart-type FABP (encoded by FABP3), epidermal-type FABP (encoded by FABP5), and ileal-type FABP (encoded by FABP6) [14]. These proteins display high-affinity binding for fatty acids and other hydrophobic ligands, facilitating the transport of lipids to the specific compartments of cells for storage or oxidation [15]. Although FABPs share a highly conserved structure, each of them has its own sequence and exhibits distinct affinity for ligand preferences [16].…”

“…The malabsorption of fatty acids in LP group could subsequently act on the nuclear receptors of PPARs, which were characterized by a DNA-binding domain and ligand-binding domains, allowing for interaction with their ligands encompassing a variety of lipid components such as fatty acids [15].…”

Transcriptome Analysis Reveals Mechanism Underlying the Differential Intestinal Functionality of Laying Hens in the Late Phase and Peak Phase of Production

“…The malabsorption of fatty acids in LP group could subsequently act on the nuclear receptors of PPARs, which were characterized by a DNA-binding domain and ligand-binding domains, allowing for interaction with their ligands encompassing a variety of lipid components such as fatty acids [24].…”