Functions Of Fatty Acid-binding Proteins Research Articles

Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition.

The family of intracellular lipid binding proteins (iLBPs) is comprised of 16 members of structurally related binding proteins that have ubiquitous tissue expression in humans. iLBPs collectively bind diverse essential endogenous lipids and xenobiotics. iLBPs solubilize and traffic lipophilic ligands through the aqueous milieu of the cell. Their expression is correlated with increased rates of ligand uptake into tissues and altered ligand metabolism. The importance of iLBPs in maintaining lipid homeostasis is well established. Fatty acid binding proteins (FABPs) make up the majority of iLBPs and are expressed in major organs relevant to xenobiotic absorption, distribution, and metabolism. FABPs bind a variety of xenobiotics including nonsteroidal anti-inflammatory drugs, psychoactive cannabinoids, benzodiazepines, antinociceptives, and peroxisome proliferators. FABP function is also associated with metabolic disease, making FABPs currently a target for drug development. Yet the potential contribution of FABP binding to distribution of xenobiotics into tissues and the mechanistic impact iLBPs may have on xenobiotic metabolism are largely undefined. This review examines the tissue-specific expression and functions of iLBPs, the ligand binding characteristics of iLBPs, their known endogenous and xenobiotic ligands, methods for measuring ligand binding, and mechanisms of ligand delivery from iLBPs to membranes and enzymes. Current knowledge of the importance of iLBPs in affecting disposition of xenobiotics is collectively described. SIGNIFICANCE STATEMENT: The data reviewed here show that FABPs bind many drugs and suggest that binding of drugs to FABPs in various tissues will affect drug distribution into tissues. The extensive work and findings with endogenous ligands suggest that FABPs may also alter the metabolism and transport of drugs. This review illustrates the potential significance of this understudied area.

Chewing the fat on an emerging target in multiple sclerosis.

In this article of EBioMedicine, An Cheng and colleagues show that blocking the function of fatty acid-binding proteins (FABPs) pharmacologically, alleviates the severity of the inflammatory demyelinating neurological condition in the experimental autoimmune encephalomyelitis (EAE) mouse model [1]. Suggesting that targeting lipid metabolism may be a viable therapeutic strategy against several pathological hallmarks of multiple sclerosis (MS). To appreciate this finding, we need to examine the role of FABP and its relationship with MS.

GENE EXPRESSION LEVEL, IMMUNOLOCALIZATION, AND FUNCTION OF FATTY ACID-BINDING PROTEIN FROM SCHISTOSOMA JAPONICUM.

The Schistosoma japonicum fatty acid-binding protein (FABP) is used in the cell membrane to absorb and transport fatty acids, which cannot be resynthesized by the organism and combined with hydrophobic ligands. Among the 5 stages of the worm life cycle examined, FABP messenger ribonucleic acid (mRNA) expression was highest in male adult worms, followed by the liver-stage schistosome, and was the lowest in the lung-stage schistosome. The fabp gene-coding region was cloned and expressed to obtain recombinant S. japonicum FABP (rSjFABP) with a molecular weight of approximately 18 kDa. Mice were then immunized against rSjFABP to prepare anti-FABP serum. Using immunohistochemical techniques, FABP protein was found to localize to the eggshell, parenchyma, and digestive tract. Double-stranded RNA-mediated knockdown of FABP mRNA by RNA interference decreased the number of transcripts by >70%. Moreover, the egg production rate decreased, whereas the abnormal egg ratio was significantly increased in the FABP-silenced group compared with the negative control group (P < 0.05). These results demonstrate that FABP localizes in adults and in various stages. FABP contributes to the egg-laying capacity of adults, which may be related to the reproductive function of S. japonicum.

Possible involvement of fatty acid binding proteins in psychiatric disorders

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function. Increasing evidence has shown that an imbalance of PUFAs is associated with various human psychiatric disorders, including autism and schizophrenia. However, the mechanisms underlying the effects of PUFAs on brain functions at cellular and molecular levels remain unclear. Since PUFAs are insoluble in water, specific transporters are required to deliver PUFAs to appropriate intracellular compartments. Fatty acid-binding proteins (FABPs), the cellular chaperones of PUFAs, are involved in PUFA intracellular trafficking, signal transduction, and gene transcription. Therefore, we focused on the relationship between FABP-regulated PUFA homeostasis in the brain and neuronal plasticity. The authors previously reported that FABP3, which preferentially binds to n-6 PUFAs, is strongly expressed in the gamma-aminobutyric acid (GABAergic) inhibitory interneurons of the adult mouse anterior cingulate cortex (ACC), which is a component of the limbic cortex and is important for the coordination of cognitive and emotional behaviors. Interestingly, Fabp3 KO mice show increased GABA synthesis and abnormal excitatory/inhibitory balance in the ACC. In addition, studies have indicated that FABP7, which preferentially binds to n-3 PUFAs, controls lipid raft function in astrocytes, and astrocytic Fabp7 deficiency results in an altered response of astrocytes to external stimuli. Furthermore, Fabp7 KO mice exhibit aberrant dendritic morphology, and decreased spine density and excitatory synaptic transmission in pyramidal neurons. This review summarizes relationship between PUFAs or FABPs and human psychiatric disorders and discusses recent progress in elucidating the function of FABPs, especially FABP3 and 7, in the brain.

Application of target repositioning and in silico screening to exploit fatty acid binding proteins (FABPs) from Echinococcus multilocularis as possible drug targets.

Fatty acid binding proteins (FABPs) are small intracellular proteins that reversibly bind fatty acids and other hydrophobic ligands. In cestodes, due to their inability to synthesise fatty acids and cholesterol de novo, FABPs, together with other lipid binding proteins, have been proposed as essential, involved in the trafficking and delivery of such lipophilic metabolites. Pharmacological agents that modify specific parasite FABP function may provide control of lipid signalling pathways, inflammatory responses and metabolic regulation that could be of crucial importance for the parasite development and survival. Echinococcus multilocularis and Echinococcus granulosus are, respectively, the causative agents of alveolar and cystic echinococcosis (or hydatidosis). These diseases are included in the World Health Organization's list of priority neglected tropical diseases. Here, we explore the potential of FABPs from cestodes as drug targets. To this end, we have applied a target repurposing approach to identify novel inhibitors of Echinococcus spp. FABPs. An ensemble of computational models was developed and applied in a virtual screening campaign of DrugBank library. 21 hits belonging to the applicability domain of the ensemble models were identified, and 3 of the hits were assayed against purified E. multilocularis FABP, experimentally confirming the model's predictions. Noteworthy, this is to our best knowledge the first report on isolation and purification of such four FABP, for which initial structural and functional characterization is reported here.

SnapShot: FABP Functions

Fatty acid binding proteins (FABPs) serve as intracellular chaperones for fatty acids and other hydrophobic ligands inside cells. Recent studies have demonstrated new functions of individual members of the FABP family. This Snapshot describes the overall functions of FABPs in health and disease and highlights emerging roles of adipose FABP (A-FABP) and epidermal FABP (E-FABP) in the fields of obesity, chronic inflammation, and cancer development. To view this SnapShot, open or download the PDF.

Fatty acid-binding proteins 5 and 7 gene deletion increases sucrose consumption and diminishes forced swim immobility time.

Inhibition and genetic deletion of fatty acid-binding proteins (FABPs) 5 and 7 have been shown to increase the levels of the endocannabinoid anandamide as well as the related N-acylethanolamine's palmitoylethanolamide and oleoylethanolamide. This study examined the role of these FABPs on forced-swim (FS) behavior and on sucrose consumption in two experiments: (experiment 1) using wild-type (WT) mice treated with the FABP inhibitor SBFI26 or vehicle and (experiment 2) using WT and FABP5/7 deficient mice. Results from experiment 1 showed that acute treatment with SBFI26 did not have any effect on sucrose intake or FS behavior in mice. In experiment 2, male and female FABP5/7 deficient mice showed significant increases in sucrose consumption (25 and 21%, respectively) compared with their WT counterparts. In addition, immobility time during the FS was decreased by 27% in both male and female FABP5/7 knockout mice compared with their WT counterparts. The fact that such differences were seen between the acute pharmacological approach and the genetic approach (gene deletion) of FABP needs to be further investigated. The function of FABPs and their specific effects on endocannabinoid anandamide, oleoylethanolamide, and palmitoylethanolamide may play an important role in the development of reward and mood behaviors and could provide opportunities for potential therapeutic targets.

Fatty acid binding proteins (FABPs) – a new laboratory biomarker for kidney diseases

Fatty acid binding proteins (FABPs) are a family of intracellular proteins involved in metabolism of lipids. By regulating the intracellular level of free fatty acids, those proteins indirectly influence intracellular signaling pathways. FABPs also play a role in regulation of cell growth and differentiation, and exert a significant antioxidant effect. Some reports suggest that FABPs are released by various organs (heart, liver, intestines, kidneys) in response to tissue damage. The article briefly summarizes the structure, classification and function of FABPs and discusses the applicability of liver- (L-FABP) and heart-type (H-FABP) FABPs in laboratory diagnosis of selected clinical entities, particularly kidney diseases.

Fatty acid binding protein regulate antimicrobial function via Toll signaling in Chinese mitten crab

Fatty acid binding proteins (FABPs) are members of the lipid binding protein superfamily and play crucial role in fatty acid transport and lipid metabolism. In macrophages, Adipocyte-type FABP is an important mediator of inflammation. However, the immune functions of FABPs in invertebrates are not well understood; here, we obtained the gene structure of Eriocheir sinensis FABP 3 and FABP 9 (EsFABP 3 and EsFABP 9), and compared with EsFABP 10. The mRNA expression profiles show that all three FABPs were significantly up-regulated in hemocytes after being challenged with bacteria. Of the three, EsFABP 3 was the most stable and also the most highly up-regulated. Further studies showed that knockdown of EsFABP 3 led to higher bacterial counts in the hemocyte culture medium and a significant decrease in the mRNA expression of some antimicrobial peptides following bacterial stimulation. Moreover, a subcellular study demonstrated that EsFABP 3 can affect nuclear translocation of the dorsal after Gram-positive bacterial stimulation in hemocytes. These findings support the notion that EsFABP 3 could inhibit bacterial proliferation by regulating antimicrobial peptides expression via the Toll signaling pathway.

Metabolic functions of FABPs--mechanisms and therapeutic implications.

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.

Fatty acid binding protein FABP3 from Chinese mitten crab Eriocheir sinensis participates in antimicrobial responses

Intracellular fatty acid-binding proteins (FABPs) are members of the lipid-binding protein superfamily. Aside from the main functions of FABPs in the uptake and transport of fatty acids, they are also critical in innate immunology. In this work, the full-length cDNA for a Chinese mitten crab Eriocheir sinensis FABP (Es-FABP3) was cloned with an open reading frame of 402 bp encoding a 133 amino acid polypeptide. Analysis using quantitative real-time PCR (qPCR) revealed that Es-FABP3 transcripts were widely distributed in gills, muscle, intestine, hepatopancreas, eyestalk, heart, stomach, brain, thoracic ganglia and hemocytes. After challenge with pathogen associated molecular pattern molecules (PAMPs), the relative mRNA expression levels of Es-FABP3 increased in hepatopancreas, gills and hemocytes. Moreover, the mature recombinant Es-FABP3 protein exhibited different binding activities to bacteria and fungus and inhibited the growth of different microbes. These collective results demonstrated the role of Es-FABP3 in the immunoreactions of E. sinensis to PAMPs.

Fatty acid binding protein 3 (fabp3) is associated with insulin, lipids and cardiovascular phenotypes of the metabolic syndrome through epigenetic modifications in a northern european family population

BackgroundFatty acid-binding proteins (FABPs) play regulatory roles at the nexus of lipid metabolism and signaling. Dyslipidemia in clinical manifestation frequently co-occurs with obesity, insulin resistance and hypertension in the Metabolic Syndrome (MetS). Animal studies have suggested FABPs play regulatory roles in expressing MetS phenotypes. In our family cohort of Northern European descent, transcript levels in peripheral white blood cells (PWBCs) of a key FABPs, FABP3, is correlated with the MetS leading components. However, evidence supporting the functions of FABPs in humans using genetic approaches has been scarce, suggesting FABPs may be under epigenetic regulation. The objective of this study was to test the hypothesis that CpG methylation status of a key regulator of lipid homeostasis, FABP3, is a quantitative trait associated with status of MetS phenotypes in humans.MethodsWe used a mass-spec based quantitative method, EpiTYPER®, to profile a CpG island that extends from the promoter to the first exon of the FABP3 gene in our family-based cohort of Northern European descent (n=517). We then conducted statistical analysis of the quantitative relationship of CpG methylation and MetS measures following the variance-component association model. Heritability of each methylation and the effect of age and sex on CpG methylation were also assessed in our families.ResultsWe find that methylation levels of individual CpG units and the regional average are heritable and significantly influenced by age and sex. Regional methylation was strongly associated with plasma total cholesterol (p=0.00028) and suggestively associated with LDL-cholesterol (p=0.00495). Methylation at individual units was significantly associated with insulin sensitivity, lipid particle sizing and diastolic blood pressure (p<0.0028, corrected for multiple testing for each trait). Peripheral white blood cell (PWBC) expression of FABP3 in a separate group of subjects (n=128) negatively correlated with adverse profiles of metabolism (βWHR = −0.72; βLDL-c = −0.53) while positively correlated with plasma adiponectin (β=0.24). Further, we show that differential methylation of FABP3 affects binding activity with nuclear proteins from heart tissue. This region that we found under methylation regulation overlaps with a region actively modified by histone codes in the newly available ENCODE data.ConclusionsOur findings suggest that DNA methylation of FABP3 strongly influences MetS, and this may have important implications for cardiovascular disease.

Fatty Acid Binding Proteins FABP9 and FABP10 Participate in Antibacterial Responses in Chinese Mitten Crab, Eriocheir sinensis

Invertebrates rely solely on the innate immune system for defense against pathogens and other stimuli. Fatty acid binding proteins (FABP), members of the lipid binding proteins superfamily, play a crucial role in fatty acid transport and lipid metabolism and are also involved in gene expression induced by fatty acids. In the vertebrate immune system, FABP is involved in inflammation regulated by fatty acids through its interaction with peroxidase proliferator activate receptors (PPARs). However, the immune functions of FABP in invertebrates are not well characterized. For this reason, we investigated the immune functionality of two fatty acid binding proteins, Es-FABP9 and Es-FABP10, following lipopolysaccharide (LPS) challenge in the Chinese mitten crab (Eriocheir sinensis). An obvious variation in the expression of Es-FABP9 and Es-FABP10 mRNA in E. sinensis was observed in hepatopancreas, gills, and hemocytes post-LPS challenge. Recombinant proteins rEs-FABP9 and rEs-FABP10 exhibited distinct bacterial binding activity and bacterial agglutination activity against Escherichia coli and Staphylococcus aureus. Furthermore, bacterial growth inhibition assays demonstrated that rEs-FABP9 responds positively to the growth inhibition of Vibrio parahaemolyticuss and S. aureus, while rEs-FABP10 responds positively to the growth inhibition of Aeromonas hydrophila and Bacillus subtilis. Coating of agarose beads with recombinant rEs-FABP9 and rEs-FABP10 dramatically enhanced encapsulation of the beads by crab hemocytes in vitro. In conclusion, the data presented here demonstrate the participation of these two lipid metabolism-related proteins in the innate immune system of E. sinensis.

Comparative Study of the Fatty Acid Binding Process of a New FABP from Cherax quadricarinatus by Fluorescence Intensity, Lifetime and Anisotropy

Fatty acid-binding proteins (FABPs) are small cytosolic proteins, largely distributed in invertebrates and vertebrates, which accomplish uptake and intracellular transport of hydrophobic ligands such as fatty acids. Although long chain fatty acids play multiple crucial roles in cellular functions (structural, energy metabolism, regulation of gene expression), the precise functions of FABPs, especially those of invertebrate species, remain elusive. Here, we have identified and characterized a novel FABP family member, Cq-FABP, from the hepatopancreas of red claw crayfish Cherax quadricarinatus. We report the characterization of fatty acid-binding affinity of Cq-FABP by four different competitive fluorescence-based assays. In the two first approaches, the fluorescent probe 8-Anilino-1-naphthalenesulfonate (ANS), a binder of internal cavities of protein, was used either by directly monitoring its fluorescence emission or by monitoring the fluorescence resonance energy transfer occurring between the single tryptophan residue of Cq-FABP and ANS. The third and the fourth approaches were based on the measurement of the fluorescence emission intensity of the naturally fluorescent cis-parinaric acid probe or the steady-state fluorescence anisotropy measurements of a fluorescently labeled fatty acid (BODIPY-C16), respectively. The four methodologies displayed consistent equilibrium constants for a given fatty acid but were not equivalent in terms of analysis. Indeed, the two first methods were complicated by the existence of non specific binding modes of ANS while BODIPY-C16 and cis-parinaric acid specifically targeted the fatty acid binding site. We found a relationship between the affinity and the length of the carbon chain, with the highest affinity obtained for the shortest fatty acid, suggesting that steric effects primarily influence the interaction of fatty acids in the binding cavity of Cq-FABP. Moreover, our results show that the binding affinities of several fatty acids closely parallel their prevalences in the hepatopancreas of C. quadricarinatus as measured under specific diet conditions.

Fatty Acid Binding Proteins and Cardiovascular Risk

The role of fatty acid-binding proteins in cardiovascular disease has been the subject of several studies and viewpoints in recent years. These proteins are involved in the atherosclerotic plaque formation mainly in macrophages through a complex processing of lipids and inflammatory responses. In addition, they may signal the presence of obesity, insulin resistance, and type 2 diabetes mellitus, co-morbidities with a demonstrated impact in cardiovascular risk. The present review aims to summarize the most relevant findings over the past years to the function of fatty acid-binding proteins (FABPs) along the spectrum of metabolic disorders and cardiovascular disease. Finally, we will discuss the potential use of FABPs as cardiovascular risk markers and therapeutic targets to halt the progression of atherosclerosis.

Fatty Acid-binding Proteins Transport N-Acylethanolamines to Nuclear Receptors and Are Targets of Endocannabinoid Transport Inhibitors

N-acylethanolamines (NAEs) are bioactive lipids that engage diverse receptor systems. Recently, we identified fatty acid-binding proteins (FABPs) as intracellular NAE carriers. Here, we provide two new functions for FABPs in NAE signaling. We demonstrate that FABPs mediate the nuclear translocation of the NAE oleoylethanolamide, an agonist of nuclear peroxisome proliferator-activated receptor α (PPARα). Antagonism of FABP function through chemical inhibition, dominant-negative approaches, or shRNA-mediated knockdown reduced PPARα activation, confirming a requisite role for FABPs in this process. In addition, we show that NAE analogs, traditionally employed as inhibitors of the putative endocannabinoid transmembrane transporter, target FABPs. Support for the existence of the putative membrane transporter stems primarily from pharmacological inhibition of endocannabinoid uptake by such transport inhibitors, which are widely employed in endocannabinoid research despite lacking a known cellular target(s). Our approach adapted FABP-mediated PPARα signaling and employed in vitro binding, arachidonoyl-[1-(14)C]ethanolamide ([(14)C]AEA) uptake, and FABP knockdown to demonstrate that transport inhibitors exert their effects through inhibition of FABPs, thereby providing a molecular rationale for the underlying physiological effects of these compounds. Identification of FABPs as targets of transport inhibitors undermines the central pharmacological support for the existence of an endocannabinoid transmembrane transporter.

Discrete localization of various fatty-acid-binding proteins in various cell populations of mouse retina

Various fatty acids (FAs) are involved as an energy source in many different functions in the organism. They are also essential ingredients of membranous lipids and act as intracellular signaling molecules. Intracellular fatty-acid-binding proteins (FABPs) comprise a family of soluble lipid-binding proteins with low molecular masses and solubilize long-chain FAs to allow intracellular translocation in the aqueous cytosol. To clarify the functions of FABPs in the retina, which is remarkably rich in polyunsaturated FAs, we have investigated the localization of B (brain type)-, H (heart type)-, E (epidermal type)-, and A (adipocyte type)-FABPs in adult mouse retinae by immunohistochemistry. In order to determine the possible involvement of FABPs in retinal degenerative diseases, we have also examined changes in FABP expression in light-induced photoreceptor cell degeneration (photic injury). The discrete localization of B-, H-, E-, and A-FABP species in various cell populations of the retina has been clarified: B-FABP is mainly localized in the cone photoreceptor cells, H-FABP in some populations of amacrine/bipolar/horizontal interneurons, and E-FABP in ganglion cells, with A-FABP-like immunoreactivity being located in resident microglia of normal retinae. E-FABP has further been localized in invasive macrophages in damaged retinae following photic injury, allowing discrete identification of the resident microglia and invasive macrophages by A- and E-FABP immunoreactivity, respectively.

Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets

Lipids are vital components of many biological processes and crucial in the pathogenesis of numerous common diseases, but the specific mechanisms coupling intracellular lipids to biological targets and signalling pathways are not well understood. This is particularly the case for cells burdened with high lipid storage, trafficking and signalling capacity such as adipocytes and macrophages. Here, we discuss the central role of lipid chaperones--the fatty acid-binding proteins (FABPs)--in lipid-mediated biological processes and systemic metabolic homeostasis through the regulation of diverse lipid signals, and highlight their therapeutic significance. Pharmacological agents that modify FABP function may provide tissue-specific or cell-type-specific control of lipid signalling pathways, inflammatory responses and metabolic regulation, potentially providing a new class of drugs for diseases such as obesity, diabetes and atherosclerosis.

Fatty Acid Binding Protein: Localization and Functional Significance in the Brain

Long chain fatty acids are important nutrients for brain development and function. However, the molecular basis of their actions in the brain is still to be clarified. Fatty acid-binding proteins (FABPs) belong to the multigene family of the intracellular lipid-binding protein. FABPs bind to long chain fatty acids, being involved in the promotion of cellular uptake and transport of fatty acids, the targeting of fatty acids to specific metabolic pathways, and the regulation of gene expression. FABPs are widely expressed in mammalian tissues, with distinct expression patterns for the individual protein. Although FABPs have been implicated to serve as regulators in systemic cellular metabolic pathways, recent studies have demonstrated the ability of FABPs to regulate functions of the brain, one of the most fat-enriched tissues in the body. This review summarizes the localization of FABPs in the brain, and recent progress in elucidating the function of FABPs in the brain.

Adipocyte/macrophage fatty acid binding proteins in metabolic syndrome

The link between inflammation and the development of insulin resistance, type 2 diabetes, and atherosclerosis has been uncovered in the past decade. Although the molecular mechanisms underlying the co-occurrence of these metabolic and inflammatory diseases are not fully understood, several molecular players, integrating stress and inflammatory responses with metabolic homeostasis, were discovered recently. One of these molecular integration sites is through the action of cytosolic lipid chaperones or fatty acid binding proteins (FABPs), which are common to adipocytes and macrophages. Furthermore, studies in a variety of genetic models demonstrated that the FABPs aP2 and mal1 are critical mediators of many components of metabolic syndrome in mice. These exciting findings raise the possibility that FABPs represent desirable therapeutic targets for metabolic syndrome. In this review, we describe the findings demonstrating FABP's role in metabolic and inflammatory diseases and highlight recent advances in understanding the mechanisms of FABP function at the cellular and molecular level.