Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier.

AIMS: Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS. Experiments were designed to determine whether or not A-FABP mediates blood-brain barrier (BBB) disruption, and if so, to explore the molecular mechanisms underlying this deleterious effects. METHODS AND RESULTS: Circulating A-FABP and its cerebral expression were increased in mice after middle cerebral artery occlusion. Genetic deletion and pharmacological inhibition of A-FABP alleviated cerebral ischaemia injury with reduced infarction volume, cerebral oedema, neurological deficits, and neuronal apoptosis; BBB disruption was attenuated and accompanied by reduced degradation of tight junction proteins and induction of matrix metalloproteinases-9 (MMP-9). In patients with acute IS, elevated circulating A-FABP levels positively correlated with those of MMP-9 and cerebral infarct volume. Mechanistically, ischaemia-induced elevation of A-FABP selectively in peripheral blood monocyte-derived macrophages and cerebral resident microglia promoted MMP-9 transactivation by potentiating JNK/c-Jun signalling, enhancing degradation of tight junction proteins and BBB leakage. The detrimental effects of A-FABP were prevented by pharmacological inhibition of MMP-9. CONCLUSION: A-FABP is a key mediator of cerebral ischaemia injury promoting MMP-9-mediated BBB disruption. Inhibition of A-FABP is a potential strategy to improve IS outcome.

A-FABP in Metabolic Diseases and the Therapeutic Implications: An Update.

Adipocyte fatty acid-binding protein (A-FABP), which is also known as ap2 or FABP4, is a fatty acid chaperone that has been further defined as a fat-derived hormone. It regulates lipid homeostasis and is a key mediator of inflammation. Circulating levels of A-FABP are closely associated with metabolic syndrome and cardiometabolic diseases with imminent diagnostic and prognostic significance. Numerous animal studies have elucidated the potential underlying mechanisms involving A-FABP in these diseases. Recent studies demonstrated its physiological role in the regulation of adaptive thermogenesis and its pathological roles in ischemic stroke and liver fibrosis. Due to its implication in various diseases, A-FABP has become a promising target for the development of small molecule inhibitors and neutralizing antibodies for disease treatment. This review summarizes the clinical and animal findings of A-FABP in the pathogenesis of cardio-metabolic diseases in recent years. The underlying mechanism and its therapeutic implications are also highlighted.

3D-QSAR assisted identification of FABP4 inhibitors: An effective scaffold hopping analysis/QSAR evaluation.

Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC50 values between 3.70 and 5.59 µM, with a high level of agreement with the predicted values.

Computational Tools in the Discovery of FABP4 Ligands: A Statistical and Molecular Modeling Approach.

Small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have received interest following the recent publication of their pharmacologically beneficial effects. Recently, it was revealed that FABP4 is an attractive molecular target for the treatment of type 2 diabetes, other metabolic diseases, and some type of cancers. In past years, hundreds of effective FABP4 inhibitors have been synthesized and discovered, but, unfortunately, none have reached the clinical research phase. The field of computer-aided drug design seems to be promising and useful for the identification of FABP4 inhibitors; hence, different structure- and ligand-based computational approaches have been used for their identification. In this paper, we searched for new potentially active FABP4 ligands in the Marine Natural Products (MNP) database. We retrieved 14,492 compounds from this database and filtered through them with a statistical and computational filter. Seven compounds were suggested by our methodology to possess a potential inhibitory activity upon FABP4 in the range of 97-331 nM. ADMET property prediction was performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives. From these analyses, three molecules that are excellent candidates for becoming new drugs were found.

Association of A-FABP gene polymorphism and mRNA expression with intramuscular fat content (IMF) in Baicheng-You chicken.

This study aims to assess the association of polymorphisms and mRNA expression of adipocyte-type fatty acid-binding protein (A-FABP) with intramuscular fat (IMF) in the breast muscle (BM) and leg muscle (LM) of Baicheng-You chickens (BYCs). A total of 180 chickens, including sixty black Baicheng-You chickens (BBYCs), sixty silky Baicheng-You chickens (SBYCs) and sixty white Baicheng-You chickens (WBYCs), were reared from 1 to 120 day. A polymerase chain reaction-single-strand conformation polymorphism strategy (PCR-SSCP) was used to detect the polymorphism of the A-FABP gene in the first exon, and the C51T silent mutational site was found. The IMF content with the AA genotype was significantly higher than that with the AG genotype (p = 0.0473) in the LM of WBYC. Thus, this site could be taken as a molecular marker in selecting a higher IMF content of LM in WBYC. A-FABP gene mRNA expression in the BM and LM of BYCs was detected, and a significant positive correlation was observed in the LM of WBYC. These findings provide fundamental data that might be useful in further study of the role of the A-FABP gene in IMF content and fatty metabolism in chickens.

Down-regulation of A-FABP predicts non-muscle invasive bladder cancer progression: investigation with a long term clinical follow-up.

BACKGROUND: Non-muscle invasive bladder cancers (NMIBC: pTa, pT1) are characterised by a high risk of recurrence and/or progression. Identification of prognostic markers is needed to improve both diagnosis and management of the disease. The aim of this study was to analyse the expression of A-FABP (adipocyte-fatty acid binding protein) and to evaluate its prognostic value in bladder cancer with a long term clinical follow-up. METHODS: A-FABP expression was investigated by immunohistochemistry in 236 tumours (114 pTa, 61 pT1, 61 pT2-4). Immunostaining was classified as negative (absent or weak immunostaining and moderate or strong staining on ≤10% of cells) or positive (moderate or strong staining on > 10% of cells). Event-free survival (EFS) and overall survival (OS) were determined with a 87.3 months median follow-up in the overall cohort. Recurrence-free survival (RFS) and progression-free survival (PFS) were established in NMIBC. RESULTS: Loss of A-FABP was associated with higher mean age, high stage/grade, and the presence of metastatic lymph nodes. It was correlated with shorter median EFS (17.5 vs 62.5 months; p = 0.001) and mean OS (76.7 vs 154.2 months; p = 0.009) and with higher risk of progression in the pTa/pT1 subgroup (HR, 0.36; 95% CI, 0.13-0.96; p = 0.041) and importantly in the pTa tumours (HR, 0.34; 95% CI, 0.10-0.97; p = 0.045). CONCLUSION: These results demonstrated that loss of A-FABP expression following a long follow-up was predictive of pTa and pTa/pT1 progression. Immunohistochemistry on diagnostic biopsy is easy to use and could be of value to help clinicians to propose appropriate treatment for these tumours.

Screening somatic cell nuclear transfer parameters for generation of transgenic cloned cattle with intragenomic integration of additional gene copies that encode bovine adipocyte-type fatty acid-binding protein (A-FABP).

Somatic cell nuclear transfer (SCNT) is frequently used to produce transgenic cloned livestock, but it is still associated with low success rates. To our knowledge, we are the first to report successful production of transgenic cattle that overexpress bovine adipocyte-type fatty acid binding proteins (A-FABPs) with the aid of SCNT. Intragenomic integration of additional A-FABP gene copies has been found to be positively correlated with the intramuscular fat content in different farm livestock species. First, we optimized the cloning parameters to produce bovine embryos integrated with A-FABP by SCNT, such as applied voltage field strength and pulse duration for electrofusion, morphology and size of donor cells, and number of donor cells passages. Then, bovine fibroblast cells from Qinchuan cattle were transfected with A-FABP and used as donor cells for SCNT. Hybrids of Simmental and Luxi local cattle were selected as the recipient females for A-FABP transgenic SCNT-derived embryos. The results showed that a field strength of 2.5 kV/cm with two 10-µs duration electrical pulses was ideal for electrofusion, and 4-6th generation circular smooth type donor cells with diameters of 15-25 µm were optimal for producing transgenic bovine embryos by SCNT, and resulted in higher fusion (80%), cleavage (73%), and blastocyst (27%) rates. In addition, we obtained two transgenic cloned calves that expressed additional bovine A-FABP gene copies, as detected by PCR-amplified cDNA sequencing. We proposed a set of optimal protocols to produce transgenic SCNT-derived cattle with intragenomic integration of ectopic A-FABP-inherited exon sequences.

Correlation of the A-FABP Gene Polymorphism and mRNA Expression with Intramuscular Fat Content in Three-Yellow Chicken and Hetian-Black Chicken.

The adipocyte-type fatty acid-binding protein (A-FABP) is considered a candidate gene for fat metabolism; thus, it affects fat deposition in chickens. The present study was designed to examine the polymorphism and mRNA abundance of the A-FABP gene with intramuscular fat (IMF) in the pectoralis muscles (PM) and leg muscles (LM) of Three-yellow Chicken (TYC) and Hetian-black Chicken (HTBC). In total, 60 TYCs and 60 HTBCs were sacrificed using exsanguination at market age. The IMF contents of the PM and LM in the HTBC were significantly higher than those in the TYC. Three genotypes of the A-FABP gene first exon, AA, AB, and BB, were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), and a C51 T mutational site, which is a silent substitution mutation, was revealed. The IMF contents of the AA genotype in the PM of the HTBC were significantly higher than those in the AB genotype; thus, the C51 T mutable site is a gene marker for selecting a higher IMF content in the PM of the HTBC. The relative expression of the A-FABP mRNA in the LM of the HTBC, which was measured by quantitative real-time PCR, was significantly higher than in the TYC. A significantly positive association was detected between A-FABP expression with the IMF contents of the PM and LM of both the TYC and the HTBC. These results provide basic data that might be helpful to further research the role of the A-FABP gene in fat deposition and fatty acid metabolism in chickens.

Levofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP.

Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.

Elevated Serum Concentration of Adipocyte Fatty Acid-Binding Protein Correlates with the Markers of Abdominal Obesity Independently of Thyroid Hormones in Non-Obese Women with Polycystic Ovary Syndrome.

Adipocyte fatty acid-binding protein (A-FABP) is mainly expressed in adipocytes. The risk of abdominal obesity and autoimmune thyroid disease is increased in women with polycystic ovary syndrome (PCOS). The objective of this study was to explore the relationship of serum concentration of A-FABP with parameters of obesity, e.g., waist to hip ratio (WHR) and the amount of adipose tissue assessed by bioelectrical impedance analysis (BIA), and thyroid hormone homeostasis in women with PCOS. We examined 66 women with PCOS and 67 healthy women. Serum concentrations of A-FABP and thyroid hormones were measured; the FT3/FT4 ratio, thyroid-stimulating hormone index (TSHI), thyrotrope thyroxine resistance index (TT4RI) and thyroid feedback quantile-based index (TFQI) were calculated. In the PCOS group, serum concentrations of A-FABP, FT3 and the FT3/FT4 ratio were significantly higher in comparison to the control group (all p < 0.05). A correlation of A-FABP with WHR (r = 0.26, p = 0.04) and the percentage of adipose tissue (r = 0.33, p = 0.01) has been found only in women with PCOS. We observed no correlation between serum levels of A-FABP and TSHI, TT4RI or TFQI in women with PCOS (all p > 0.05). Our results indicate that A-FABP is an adipokine that may be connected with abdominal obesity independently of thyroid hormone homeostasis in PCOS patients.

Adipocyte fatty acid binding protein 4 (FABP4) inhibitors. An update from 2017 to early 2022.

The fatty acid binding protein 4 (FABP4) is a protein predominantly expressed in macrophages and adipose tissue, where it regulates fatty acids storage and lipolysis and is an essential mediator of inflammation. Small molecule inhibitors of FABP4 have attracted interest following the recent publications of beneficial pharmacological effects of these compounds for the treatment of metabolic syndrome and, more recently, for other pathologies. Since the synthesis of the BMS309403, one of the first selective and effective FABP4 inhibitors, hundreds of other inhibitors have been synthesized (i.e., derivatives of niacin, quinoxaline, aryl-quinoline, bicyclic pyridine, urea, aromatic compounds and other novel heterocyclic compounds). This review updates the recently reported (2017 to early 2022) molecules as adipocyte fatty acid binding protein 4 inhibitors.

A-FABP-PTEN/AKT Regulates Insulin Resistance in Preadipocyte Cell 3T3-L1 Cells.

OBJECTIVE: The purpose of this study was to explore the regulation of A-FABP-PTEN/AKT on insulin resistance in preadipocyte 3T3-L1 cell. METHODS: siRNA interference method was used to knock-down the A-FABP expression in 3T3-L1 cells. The cell proliferation was detected by oil-O staining and MTT. The protein and mRNA expression levels of A-FABP, PTEN and AKT were detected by Western blot and qPCR. RESULTS: Inhibition of A-FABP expression increased cell proliferation activity of the 3T3-L1 cells. Moreover, siRNA3 significantly reduced A-FABP mRNA expression compared with siRNA1 and siRNA2 (P<0.05). The A-FABP mRNA level was significantly increased in the induced 3T3-L1 cells, while the PTEN mRNA expression was significantly decreased (P<0.05). Inhibition of A-FABP can significantly increase the PTEN mRNA expression in the process of induced 3T3-L1 cells (P<0.05). Overexpression of A-FABP can also increase the PTEN mRNA expression in the process of 3T3-L1 cell proliferation (P<0.05). Furthermore, the protein expression levels of PTEN and p-AKT expression were not changed in the process of 3T3-L1 cell proliferation with or without A-FABP interference (P>0.05). However, inhibition of A-FABP significantly increased the PTEN protein expression and reduced the p-AKT protein expression in the induced 3T3-L1 cells. CONCLUSION: Our finding suggested that A-FABP can directly inhibit the phosphorylation of AKT and increase the PTEN expression in the process of normal adipocyte differentiation, which speculated that A-FABP played a crucial role by adjusting the AKT activity in the process of adipocyte differentiation.

Adipocyte Fatty Acid Binding Protein Promotes the Onset and Progression of Liver Fibrosis via Mediating the Crosstalk between Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells.

Development of liver fibrosis results in drastic changes in the liver microenvironment, which in turn accelerates disease progression. Although the pathological function of various hepatic cells in fibrogenesis is identified, the crosstalk between them remains obscure. The present study demonstrates that hepatic expression of adipocyte fatty acid binding protein (A-FABP) is induced especially in the liver sinusoidal endothelial cells (LSECs) in mice after bile duct ligation (BDL). Genetic ablation and pharmacological inhibition of A-FABP attenuate BDL- or carbon tetrachloride-induced liver fibrosis in mice associating with reduced collagen accumulation, LSEC capillarization, and hepatic stellate cell (HSC) activation. Mechanistically, elevated A-FABP promotes LSEC capillarization by activating Hedgehog signaling, thus impairs the gatekeeper function of LSEC on HSC activation. LSEC-derived A-FABP also acts on HSCs in paracrine manner to potentiate the transactivation of transforming growth factor ß1 (TGFß1) by activating c-Jun N-terminal kinase (JNK)/c-Jun signaling. Elevated TGFß1 subsequently exaggerates liver fibrosis. These findings uncover a novel pathological mechanism of liver fibrosis in which LSEC-derived A-FABP is a key regulator modulating the onset and progression of the disease. Targeting A-FABP may represent a potential approach against liver fibrosis.

Molecular mechanisms of inhibitor bindings to A-FABP deciphered by using molecular dynamics simulations and calculations of MM-GBSA.

Adipocyte fatty-acid binding protein (A-FABP) plays a central role in many aspects of metabolic diseases. It is an important target in drug design for treatment of FABP-related diseases. In this study, molecular dynamics (MD) simulations followed by calculations of molecular mechanics generalized Born surface area (MM-GBSA) and principal components analysis (PCA) were implemented to decipher molecular mechanism correlating with binding of inhibitors 57Q, 57P and L96 to A-FABP. The results show that van der Waals interactions are the leading factors to control associations of 57Q, 57P, and L96 with A-FABP, which reveals an energetic basis for designing of clinically available inhibitors towards A-FABP. The information from PCA and cross-correlation analysis rationally unveils that inhibitor bindings affect conformational changes of A-FABP and change relative movements between residues. Decomposition of binding affinity into contributions of individual residues not only detects hot spots of inhibitor/A-FABP binding but also shows that polar interactions of the positively charged residue Arg126 with three inhibitors provide a significant contribution for stabilization of the inhibitor/A-FABP bindings. Furthermore, the binding strength of L96 to residues Ser55, Phe57 and Lys58 are stronger than that of inhibitors 57Q and 57P to these residues.

Increased Levels of Adipocyte and Epidermal Fatty Acid-Binding Proteins in Acute Lymphoblastic Leukemia Survivors.

Childhood cancer survivors are highly exposed to the development of side effects after many years of cessation of anticancer treatment, including altered lipid metabolism that may result in an increased risk of overweight and metabolic syndrome. Adipocyte (A-FABP) and epidermal (E-FABP) fatty acid-binding proteins are expressed in adipocytes and are assumed to play an important role in the development of lipid disturbances leading to the onset of metabolic syndrome. The aim of this study was to investigate the association between serum A-FABP and E-FABP levels, overweight, and components of the metabolic syndrome in acute lymphoblastic leukemia survivors. Sixty-two acute lymphoblastic leukemia (ALL) survivors (34 females) were included in the study. The mean age at the time of the study was 12.41 ± 4.98 years (range 4.71-23.43). Serum levels of A-FABP and E-FABP were analyzed using a commercially available ELISA kit. The ALL survivors presented statistically higher A-FABP levels in comparison with the healthy controls (25.57 ± 14.46 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with body mass index (BMI) above the normal range (18 overweight, 10 obese) had a greater level of A-FABP compared to the ALL group with normal BMI (32.02 ± 17.10 vs. 20.33 ± 9.24 ng/mL, p = 0.006). Of all participants, 53.23% had at least one risk factor of metabolic syndrome; in this group, only the A-FABP level showed a statistically significant difference compared to the healthy control group (30.63 ± 15.91 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with two or more metabolic risk factors (16.13%) presented higher levels of both A-FABP (33.62 ± 17.16 vs. 15.13 ± 7.61 ng/mL, p = 0.001) and E-FABP (13.37 ± 3.62 vs. 10.12 ± 3.21 ng/mL, p = 0.021) compared to the controls. Univariable regression models showed significant associations between BMI and systolic blood pressure with the A-FABP level (coeff. 1.02 and 13.74, respectively; p < 0.05). In contrast, the E-FABP level was only affected by BMI (coeff. 0.48; p < 0.01). The findings reported herein suggest that the increased levels of A-FABP and E-FABP may be involved in the pathogenesis of overweight and the onset of metabolic syndrome in acute lymphoblastic leukemia. However, further longitudinal, prospective studies of fatty acid-binding proteins and their potential role in the pathogenesis of obesity and metabolic syndrome in ALL survivors remain to be performed.

Epicardial Adiposity in Relation to Metabolic Abnormality, Circulating Adipocyte FABP, and Preserved Ejection Fraction Heart Failure.

Epicardial adipose tissue (EAT) as a source of pro-inflammatory cytokines tightly linked to metabolic abnormalities. Data regarding the associations of EAT with adipocyte fatty acid-binding protein (A-FABP), a cytokine implicated in the cardiometabolic syndrome, might play an important part in mediating the association between EAT and cardiac structure/function in preserved ejection fraction heart failure (HFpEF). We conducted a prospective cohort study comprising 252 prospectively enrolled study participants classified as healthy (n = 40), high-risk (n = 161), or HFpEF (n = 51). EAT was assessed using echocardiography and compared between the three groups and related to A-FABP, cardiac structural/functional assessment utilizing myocardial deformations (strain/strain rates) and HF outcomes. EAT thickness was highest in participants with HFpEF (9.7 ± 1.7 mm) and those at high-risk (8.2 ± 1.5 mm) and lowest in healthy controls (6.4 ± 1.9 mm, p < 0.001). Higher EAT correlated with the presence of cardiometabolic syndrome, diabetes and renal insufficiency independent of BMI and waist circumference (pinteraction for all > 0.1), and was associated with reduced LV global longitudinal strain (GLS) and LV mass-independent systolic/diastolic strain rates (SRs/SRe) (all p < 0.05). Higher A-FABP levels were associated with greater EAT thickness (pinteraction > 0.1). Importantly, in the combined control cohort, A-FABP levels mediated the association between EAT and new onset HF. Excessive EAT is independently associated with the metabolic syndrome, renal insufficiency, and higher A-FABP levels. The association between EAT and new onset HF is mediated by A-FABP, suggesting a metabolic link between EAT and HF.

Adipocyte Fatty Acid-Binding Protein as a Predictor of Outcome in Alcohol-induced Acute-On-Chronic Liver Failure.

BACKGROUND: Alcohol is the leading cause of acute-on-chronic liver failure (ACLF). Several severity scores predict the outcome of ACLF. However, there is a lack of simple biomarkers in predicting the outcome of these sick patients. Fatty acid-binding proteins (FABPs) are small cytosolic proteins that play a major role in lipid metabolism, energy homeostasis, and inflammation, but, have not been investigated in alcohol-induced ACLF (A-ACLF). OBJECTIVES: The primary objective was to assess the correlation between serum adipocyte-FABP (A-FABP) and liver-FABP (L-FABP) levels on mortality at day 90. Secondary objectives were to compare the levels between controls and A-ACLF, correlate L-FABP, and A-FABP levels on the development of organ failure/sepsis at day 90. METHODS: In this prospective observational pilot study, we included patients with A-ACLF and age-matched healthy controls. FABP's were analyzed by enzyme-linked immunosorbent assay method. The patients were followed up for 90 days. RESULTS: Twenty-five patients with A-ACLF (mean age: 40years; mean model for end-stage liver disease NA: 29.8; median Modified Maddrey's discriminant function [mDF]: 95) and 12 controls (mean age: 36.83yrs) were included in the study. A-FABP and L-FABP levels were significantly high in patients with A-ACLF than controls. Forty-four percent of patients with A-ACLF developed sepsis, 48% developed organ failure, and 44% expired by day 90. On multivariate Cox regression analysis, A-FABP (hazard ratio [HR]: 1.27 [1.08-1.5]; P = 0.003), Asian Pacific Association for the Study of Liver ACLF research consortium score (HR: 3.3[1.15-9.54]; P = 0.02), L-FABP (HR: 0.69 [0.52-0.91]; P = 0.009), and serum protein levels (HR: 0.03 [0.003-0.36]; P = 0.005) predicted mortality. A-FABP (1.17 [1.07-1.29]; P = 0.001), and serum bilirubin (1.05 [0.99-1.12]; P = 0.06) predicted development of organ failure, and only mDF (HR: 1.04 [1.01-1.07]; P = 0.009) predicted the development of sepsis on multivariate analysis. Fifteen patients received steroid therapy, of which 13.34% were nonresponders. CONCLUSIONS: In a selected group of patients with A-ACLF, A-FABP is highly sensitive at predicting mortality and outcome. If validated in a large, diverse sample, A-FABP can be used as a simple biomarker for prognostication in A-ACLF.

Adipocyte Fatty Acid-Binding Protein 4 is Altered in Growth Discordant Dichorionic, but not in Monochorionic Twins.

CONTEXT: The fetal period has a critical and long-lasting impact on the regulation of metabolic processes and a life-long predisposition for obesity and metabolic syndrome. The exact mechanisms are unknown, but epigenetic regulation likely plays a major role. Twins represent an excellent model to study these mechanisms, as they share the same intrauterine environment and similar or even the same genetic information. We examined cord blood levels of adipocyte fatty-acid binding protein 4 (A-FABP or FABP4), a novel adipokine correlated with obesity and metabolic disease in children and adults. OBJECTIVE: To examine A-FABP levels in the cord blood of twins with concordant and discordant growth and in singletons with intrauterine growth restriction (IUGR). DESIGN: Cohort study of 36 twin pairs (25 growth concordant and 11 growth discordant), and 42 singleton pregnancies (28 IUGR and 13 normally grown controls, 1 HELLP). OUTCOME MEASURES: Cord blood A-FABP levels measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: A-FABP levels were higher in the smaller of growth discordant dichorionic (DC) twins versus their co-twins (109.46 ±â€…62.80 ng/mL vs. 72.93 ±â€…36.66 ng/mL, P = 0.028). A-FABP was negatively correlated with birth weight and gestational age (P < 0.001), but not with birth weight z-score (P = 0.37). CONCLUSIONS: Increased A-FABP levels might be associated with an increased metabolic risk in growth-restricted (twins) and prematurely born infants.

A-FABP and oestrogens are independently involved in the development of breast cancer.

We previously reported that postmenopausal obese women exhibit increased levels of circulating adipocyte fatty acid binding protein (A-FABP), which is associated with breast cancer (BC) development. In postmenopause, increased oestrogen levels are reported to be associated with increased BC risk. Herein, we assessed if oestrogens, including oestrone (E1), oestradiol (E2) and oestriol (E3), are associated with A-FABP in the obesity-related BC development. We collected 249 serum samples from women with or without BC and measured serum levels of E1, E2, E3 and A-FABP. Considering all subjects, E1 and E2 but not E3 levels were significantly higher in pre- than in postmenopause individuals. E3 and E1 levels were higher in non-obese than in obese women. When samples were separated by BC status, E2 levels were significantly higher, while E1 and E3 levels were significantly lower in postmenopausal obese than non-obese women without BC. These differences based on body mass index (BMI) were not observed among women with BC. E3 levels were higher in obese women with BC than those without. A-FABP levels were significantly higher in postmenopausal obese women regardless of BC status. In addition, A-FABP was not associated with E1, E2 or E3. Altogether, our data suggest that A-FABP is independently regulated by obesity and menopausal status compared to oestrogens, thus playing a unique role in the development of BC.

Fatty Acid-Binding Protein 4 in Cardiovascular and Metabolic Diseases.

Fatty acid-binding proteins (FABPs), a family of lipid chaperones, contribute to systemic metabolic regulation via several lipid signaling pathways. Fatty acid-binding protein 4 (FABP4), known as adipocyte FABP (A-FABP) or aP2, is mainly expressed in adipocytes and macrophages and plays important roles in the development of insulin resistance and atherosclerosis in relation to metabolically driven low-grade and chronic inflammation, referred to as 'metaflammation'. FABP4 is secreted from adipocytes in a non-classical pathway associated with lipolysis and acts as an adipokine for the development of insulin resistance and atherosclerosis. Circulating FABP4 levels are associated with several aspects of metabolic syndrome and cardiovascular disease. Ectopic expression and function of FABP4 in cells and tissues are also related to the pathogenesis of several diseases. Pharmacological modification of FABP4 function by specific inhibitors, neutralizing antibodies or antagonists of unidentified receptors would be novel therapeutic strategies for several diseases, including obesity, diabetes mellitus, atherosclerosis and cardiovascular disease. Significant roles of FABP4 as a lipid chaperone in physiological and pathophysiological conditions and the possibility of FABP4 being a therapeutic target for metabolic and cardiovascular diseases are discussed in this review.