Fatty Acid Binding Proteins (FABP)

The fatty acid binding protein (FABP) family are low molecular weight (~15 kDa) soluble proteins that reversibly bind fatty acids and other lipophilic compounds enabling their movement in aqueous media. The family includes the FABP, the cellular retinoic acid binding proteins (CRABP) and the retinol binding proteins (RBP) and peripheral myelin protein 2 (PMP2). Ten FABP isoforms are known (FABP1-9 and FABP12), which share a conserved 3D structure, although sequence homology is limited. FABP have a role in the intracellular transport of endocannabinoids and endocannabinoid signaling, which are important in both the CNS and the immune system.

Crystal structure of human FABP3

Crystal structure of human FABP3. Image from the RCSB Protein Data Bank, PDB ID: 6AQ1. Yan, S. et aI. (2018) Eur J Med Chem 154 233-252.

FABP in the Nervous System

Fatty acids are important in the nervous system, having a role in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory responses. Five FABP are expressed at significant levels in the nervous system: FABP3, FABP5, FABP7 and FABP12 are expressed in the central nervous system, while FABP8 appears to be expressed almost exclusively in the peripheral nervous system.

FABP3 (previously H-FABP) is expressed in the hippocampus, cerebral neocortex, interneurons of the retina and olfactory mitral cell layer. It is highly expressed in acetylcholinergic and glutamatergic neurons of the dorsal striatum and has been shown to interact with dopamine D₂ receptors in mice. It is important in maintaining adult neurons in the differentiated state and likely has a role in Parkinson's disease and other neurodegenerative conditions.

FABP5 (E-FABP) is the most ubiquitously expressed FABP and is present in epidermis, liver, lung, adipocytes, and mammary glands. It is also the most ubiquitously expressed FABP in the CNS. During embryonic development, it is present in the brain: in the ventricular germinal zone, cerebral cortex and during stem cell differentiation to motor neurons and astrocytes. Expression of FABP5 decreases after birth and it is present at only low levels in the adult brain. It is found in retinal ganglion cells and has high affinity for Retinoic Acid (Cat. No. 0695), suggesting a role in neuronal survival and differentiation. It is also expressed under stress or pathological conditions.

FABP7 is highly expressed in the radial glia of the ventricular and subventricular zones of the embryonic brain. Expression decreases in adulthood and is found at significant levels in the Schwann cells of olfactory nerve, the radial glia of dentate gyrus, and in glial cells in the cerebellum. FABP3 and FABP7 are both found in support cells in the cochlea suggesting a role in hearing. Increased expression is found in schizophrenia, bipolar disease, and Down Syndrome.

FABP8, also known as peripheral myelin protein 2 or PMP2, is found in the myelin sheaths and Schwann cells of the peripheral nervous system and is important in the organization and stabilization of myelin layers.

FABP12 is the most recently identified of the FABPs. To date is has been found to be ubiquitously expressed in mouse brain and have a role in the protection of retinal rod cells under oxidative stress.

FABP in Metabolism and Inflammation

FABP are also mediators of metabolic and inflammatory processes and are potential targets for the development of therapies for metabolic disorders. FABP inhibitors have potential for use in a range of human disorders, including obesity, atherosclerosis, diabetes, and metabolic syndrome.

FABP1 (L-FABP) is highly expressed in hepatocytes, and is also present in enterocytes, renal tubular cells and alveolar epithelial cells. It increases cellular fatty acid uptake, mediating delivery to the nucleus, and overexpression results in increased phospholipid synthesis. FABP1 enables the cellular uptake of sterol, altering the lipid composition of the plasma membrane and increasing membrane fluidity.

FABP2 (I-FABP) is expressed in intestinal enterocytes and is important in the uptake and trafficking of lipids in the intestine. It is thought to be involved in trafficking of fatty acids towards triglycerides, rather than phospholipids. Certain genetic polymorphisms of FABP2 in humans are associated with insulin resistance, dyslipidemia and obesity. FABP1 and FABP2 may act as lipid sensors, maintaining levels of monoacylglycerols and unbound fatty acids and delivering them to protein targets.

FABP4 (A-FABP) is expressed at high levels in adipocytes in brown and white adipose tissue. It has an important role in modulating insulin secretion and lipogenesis (specifically the activation of lipolysis and suppression of lipogenesis). FABP4 is upregulated during preadipocyte differentiation but is not required for adipocyte specification. High circulating FABP4 levels are associated with increased BMI, insulin resistance and dyslipidemia, type II diabetes mellitus and hypertension. FABP4 expression is upregulated in macrophages upon inflammatory activation.

FABP5 is also important in modulating insulin sensitivity and glucose tolerance and lipogenesis.

FABP6 is expressed mainly in ileal enterocytes, but is also present in ovary, placenta and adrenal glands, and has higher affinity for bile acids than fatty acids.

FABP in Cancer

FABP may also have a role in cancer, as it has been found that overexpression of extracellular FABPs are associated with growth and invasiveness of cancers.

External sources of pharmacological information for Fatty Acid Binding Proteins (FABP) :

• IUPHAR Receptor Code