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Type 1 diabetes (T1D) is a chronic disease characterized by self-destruction of insulin-producing pancreatic β cells by cytotoxic T cell activity. However, the pathogenic mechanism of T cell infiltration remains obscure. Recently, tissue-resident memory T (T RM ) cells have been shown to contribute to cytotoxic T cell recruitment. T RM cells are found present in human pancreas and are suggested to modulate immune homeostasis. Here, the role of T RM cells in the development of T1D is investigated. The presence of T RM cells in pancreatic islets is observed in non-obese diabetic (NOD) mice before T1D onset. Mechanistically, elevated fatty acid-binding protein 4 (FABP4) potentiates the survival and alarming function of T RM cells by promoting fatty acid utilization and C-X-C motif chemokine 10 (CXCL10) secretion, respectively. In NOD mice, genetic deletion of FABP4 or depletion of T RM cells using CD69 neutralizing antibodies resulted in a similar reduction of pancreatic cytotoxic T cell recruitment, a delay in diabetic incidence, and a suppression of CXCL10 production. Thus, targeting FABP4 may represent a promising therapeutic strategy for T1D., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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.

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 β1 (TGFβ1) by activating c-Jun N-terminal kinase (JNK)/c-Jun signaling. Elevated TGFβ1 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., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing β cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level was significantly elevated in patients with type 1 diabetes and their first-degree relatives and positively correlated with the titers of several islet autoantibodies. In nonobese diabetic (NOD) mice, increased FABP4 expression in islet macrophages started from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice was markedly reduced by pharmacological inhibition or genetic ablation of FABP4 or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activated innate immune responses in islets by enhancing the infiltration and polarization of macrophages to proinflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8+ T cells and shift of CD4+ helper T cells toward Th1 subtypes. These findings demonstrate FABP4 as a possible early mediator for β cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.

Aims: To investigate determinants of circulating levels of adipocyte-fatty acid binding protein (A-FABP) and lipocalin-2 (LCN2), their relationships with cardiovascular disease (CVD) and microvascular events, and effects of fenofibrate in type 2 diabetes (T2D)., Methods: A-FABP and LCN2 were quantified in baseline plasma from 2000 T2D adults in a Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial sub-study and correlates thereof determined. In a subset (n = 200) adipokines were also measured on-trial., Results: Female sex, older age, higher body mass index (BMI), HbA1c, insulin resistance index, triglycerides, plasma creatinine and homocysteine, shorter diabetes duration, and use of oral hypoglycaemic agents alone were independent determinants of higher A-FABP. Higher BMI, fibrinogen and homocysteine, Caucasian race, and lower fasting glucose, HDL-cholesterol, apolipoprotein A-II and estimated glomerular filtration rate were independent predictors of higher LCN2 levels. Baseline A-FABP and LCN2 levels were associated with multiple new CVD and microvascular events over 5-years, though significance was lost after risk factor adjustment. Fenofibrate increased A-FABP but did not change LCN2 levels., Conclusions: Baseline plasma A-FABP and LCN2 levels were associated with concurrent CVD risk factors, and on-trial chronic complications, likely mediated via traditional risk factors. Fenofibrate increased A-FABP modestly but did not affect LCN2 levels., Clinical Trial Registration: ISRCTN 64783481., Competing Interests: Declaration of Competing Interest Fournier Pharma (now part of Abbott Pharmaceuticals) sponsored the FIELD trial but had no role in data collection, analyses or interpretation. A.J.J. has served as a diabetes advisory panel member for Abbott, Medtronic and Sanofi, has received remuneration for lectures from Novo, and has received peer-reviewed research support from Abbott and Medtronic. A.C.K. has served as an Advisory Board member for Amgen, Bayer and Sanofi, and has received speaker and/or advisor honoraria from Abbott, AstraZeneca and Pfizer, research support from Mylan, Novartis and Sanofi, and honoraria from Abbott and Amgen. R.C.M. has received research grants for clinical trials from AstraZeneca, Bayer, MSD, Novo Nordisk, Sanofi and Tricida, and honoraria for consultancy or lectures from AstraZeneca and Boehringer Ingelheim. All other authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to investigate the prospective association of circulating adipocyte fatty acid-binding protein (A-FABP) levels with the development of subclinical atherosclerosis in patients with type 2 diabetes in an 8-year prospective study., Methods: A total of 170 patients with newly diagnosed type 2 diabetes were recruited in the study and 133 patients completed the follow-up of 8 years. Baseline plasma A-FABP levels were measured with enzyme-linked immunosorbent assays. The role of A-FABP in predicting the development of subclinical atherosclerosis over 8 years was analyzed using multiple logistic regression., Results: Of the 133 patients without subclinical atherosclerosis at baseline, a total of 100 had progressed to subclinical atherosclerosis over 8 years. Baseline A-FABP level was significantly higher in patients who had progressed to subclinical atherosclerosis at year 8 compared with ones who had not developed subclinical atherosclerosis after adjustment for sex (15.3 [12.1-23.2] versus 13.3 [10.0-18.9] ng/ml, P = 0.021). High baseline A-FABP level was an independent predictor for the development of subclinical atherosclerosis in patients with type 2 diabetes (odds ratio: 16.24, P = 0.022)., Conclusions: Circulating A-FABP levels predict the development of subclinical atherosclerosis in type 2 diabetes patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The pericardial fluid may be representative of the interstitium of the heart. The aim of this study was to discriminate in cardiovascular disease patients between adipocytokines that are produced locally by the heart and those supplied by the circulation., Methods: Enzyme-linked immunosorbent assays (ELISA) were used to determine levels of N-terminal pro-brain natriuretic peptide (NT-pBNP), fatty acid-binding protein 4 (FABP4), leptin, lipocalin-2, neutrophil elastase, proteinase-3, high sensitivity C-reactive protein (hsCRP) and adiponectin in venous plasma and pericardial fluid harvested during elective cardio-thoracic surgery (n = 132-152)., Results: In pericardial fluid compared to plasma, the levels were significantly smaller (p < 0.001) for leptin, lipocalin-2, neutrophil elastase, proteinase-3, hsCRP and adiponectin. For these biomarkers, the ratio of pericardial fluid-to-plasma level ([PF]/[P], median (interquartile range)) was 0.65 (0.47-1.01), 0.78 (0.56-1.09), 0.23 (0.11-0.60), 0.17 (0.09-0.36), 0.14 (0.08-0.35), and 0.25 (0.15-0.34), respectively. In contrast, pericardial fluid was significantly enriched (p < 0.001) in NT-pBNP ([PF]/[P]: 1.9 (1.06-2.73)) and even more so for FABP4 ([PF]/[P]: 3.90 (1.47-9.77)). Moreover, in pericardial fluid, the adipocytokines interrelated all significantly positive and correlated negative to hsCRP, whereas for NT-pBNP only a significantly positive correlation with adiponectin was found. These interrelations were distinct from those in the plasma, as were the correlations of the pericardial biomarkers with patient characteristics compared to plasma., Conclusions: In cardiovascular disease patients, the pericardial cavity is a distinct adipocytokine microenvironment in which especially FABP4 is mainly derived from the heart., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Raised circulating adipocyte fatty acid-binding protein (AFABP) concentrations are associated with various adverse health conditions. However, their relationship with mortality remains to be defined, especially in view of the sexual dimorphism of circulating AFABP concentrations. Here we investigated prospectively whether serum AFABP concentrations predict multiple mortality outcomes in men and women alike, using a large clinic-based cohort of individuals with type 2 diabetes, a condition with raised AFABP concentrations., Methods: Baseline serum AFABP concentrations were measured in 5305 research participants with a monoclonal antibody-based sandwich immunoassay. The role of circulating AFABP concentrations in predicting mortality outcomes was evaluated by multivariable Cox regression analysis., Results: Among the 5305 participants (59% men) in this study, over a median follow-up of 5 years, there were 512 deaths (19.3 deaths per 1000 person-years). Circulating AFABP concentrations, with higher levels in women at baseline, predicted all-cause mortality ( P < 0.001), cardiovascular mortality ( P = 0.037), and infection-related deaths ( P < 0.002) among all participants. In sex-specific analyses, circulating AFABP concentration was an independent predictor of all-cause mortality in both men and women and a predictor of cancer-related deaths and infection-related deaths in men only. Furthermore, the addition of serum AFABP concentrations improved the time-dependent c statistics in predicting all-cause mortality in participants with type 2 diabetes ( P = 0.008)., Conclusions: Circulating AFABP concentration was an independent predictor of various mortality outcomes in type 2 diabetes over and above known risk factors of reduced survival in men and women. The role of AFABP as a prognostic biomarker and therapeutic target warrants further investigation., (© 2018 American Association for Clinical Chemistry.)

Objective- In patients with stable coronary artery disease, conventional risk factors provide limited incremental predictive value for cardiovascular events. We sought to investigate whether a panel of cardiometabolic biomarkers alone or combined with conventional risk factors would exhibit incremental value in the prediction of cardiovascular events. Approach and Results- In the discovery cohort, we measured serum adiponectin, A-FABP (adipocyte fatty acid-binding protein), lipocalin-2, FGF (fibroblast growth factor)-19 and 21, plasminogen activator inhibitor-1, and retinol-binding protein-4 in 1166 Chinese coronary artery disease patients. After a median follow-up of 35 months, 170 patients developed new-onset major adverse cardiovascular events (MACE). In the model with age ≥65 years and conventional risk factors, area under the curve for predicting MACE was 0.68. Addition of lipocalin-2 to the age-clinical risk factor model improved predictive accuracy (area under the curve=0.73). Area under the curve further increased to 0.75 when a combination of lipocalin-2, A-FABP, and FGF-19 was added to yield age-biomarkers-clinical risk factor model. The adjusted hazard ratio on MACEs for lipocalin-2, A-FABP, and FGF-19 levels above optimal cutoffs were 2.23 (95% CI, 1.62-3.08), 1.99 (95% CI, 1.43-2.76), and 1.65 (95% CI, 1.15-2.35), respectively. In the validation cohort of 1262 coronary artery disease patients with type 2 diabetes mellitus, the age-biomarkers-clinical risk factor model was confirmed to provide good discrimination and calibration over the conventional risk factor alone for prediction of MACE. Conclusions- A combination of the 3 biomarkers, lipocalin-2, A-FABP, and FGF-19, with clinical risk factors to yield the age-biomarkers-clinical risk factor model provides an optimal and validated prediction of new-onset MACE in patients with stable coronary artery disease.

Aim: To explore the role of an adipokine-termed fatty acid-binding protein 4 (FABP4) in osteoarthritis (OA)., Methods: Patients with primary knee OA and non-OA controls were included. Paired tissues including plasma, synovial fluid (SF), subcutaneous fat and infrapatellar fat pad (IPFP) were harvested during surgery. FABP4 concentration was determined by ELISA., Results: Plasma FABP4 increased significantly with OA stage (n = 263). OA patients (n = 38) had significantly higher plasma and SF FABP4 than non-OA patients (n = 29). FABP4 level of IPFP was positively correlated with SF FABP4., Conclusion: OA patients had significantly high systemic and local FABP4, and IPFP may be the main source of FABP4 in synovial cavity. FABP4 may be a promising biomarker for OA.

The adipokine adipocyte fatty acid-binding protein (A-FABP) has been implicated in obesity-related cardio-metabolic complications. Here we show that A-FABP increases thermogenesis by promoting the conversion of T4 to T3 in brown adipocytes. We find that A-FABP levels are increased in both white (WAT) and brown (BAT) adipose tissues and the bloodstream in response to thermogenic stimuli. A-FABP knockout mice have reduced thermogenesis and whole-body energy expenditure after cold stress or after feeding a high-fat diet, which can be reversed by infusion of recombinant A-FABP. Mechanistically, A-FABP induces the expression of type-II iodothyronine deiodinase in BAT via inhibition of the nuclear receptor liver X receptor α, thereby leading to the conversion of thyroid hormone from its inactive form T4 to active T3. The thermogenic responses to T4 are abrogated in A-FABP KO mice, but enhanced by A-FABP. Thus, A-FABP acts as a physiological stimulator of BAT-mediated adaptive thermogenesis., Competing Interests: The authors declare no competing financial interests.

Lipotoxicity is implicated in the pathogenesis of obesity-related inflammatory complications by promoting macrophage infiltration and activation. Endoplasmic reticulum (ER) stress and adipocyte fatty acid binding protein (A-FABP) play key roles in obesity and mediate inflammatory activity through similar signaling pathways. However, little is known about their interplay in lipid-induced inflammatory responses. Here, we showed that prolonged treatment of palmitic acid (PA) increased ER stress and expression of A-FABP, which was accompanied by reduced autophagic flux in macrophages. Over-expression of A-FABP impaired PA-induced autophagy associating with enhanced ER stress and pro-inflammatory cytokine production, while genetic ablation or pharmacological inhibition of A-FABP reversed the conditions. PA-induced expression of autophagy-related protein (Atg)7 was attenuated in A-FABP over-expressed macrophages, but was elevated in A-FABP-deficient macrophages. Mechanistically, A-FABP potentiated the effects of PA by inhibition of Janus Kinase (JAK)2 activity, thus diminished PA-induced Atg7 expression contributing to impaired autophagy and further augmentation of ER stress. These findings suggest that A-FABP acts as autophagy inhibitor to instigate toxic lipids-induced ER stress through inhibition of JAK2-dependent autophagy, which in turn triggers inflammatory responses in macrophages. A-FABP-JAK2 axis may represent an important pathological pathway contributing to obesity-related inflammatory diseases.

Clinical evidence shows that circulating levels of adipocyte fatty-acid-binding protein (A-FABP) are elevated in patients with diabetes and closely associated with ischaemic heart disease. Patients with diabetes are more susceptible to myocardial ischaemia/reperfusion (MI/R) injury. The experiments in the present study investigated the role of A-FABP in MI/R injury with or without diabetes. Non-diabetic and diabetic (streptozotocin-induced) A-FABP knockout and wild-type mice were subjected to MI/R or sham intervention. After MI/R, A-FABP knockout mice exhibited reductions in myocardial infarct size, apoptotic index, oxidative and nitrative stress, and inflammation. These reductions were accompanied by an improved left ventricular function compared with the relative controls under non-diabetic or diabetic conditions. After diabetes induction, A-FABP knockout mice exhibited a preserved cardiac function compared with that in wild-type mice. Endothelial cells, but not cardiomyocytes, were identified as the most likely source of cardiac A-FABP. Cardiac and circulating A-FABP levels were significantly increased in mice with diabetes or MI/R. Diabetes-induced superoxide anion production was significantly elevated in wild-type mice, but diminished in A-FABP knockout mice, and this elevation contributed to the exaggeration of MI/R-induced cardiac injury. Phosphorylation of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) were enhanced in both diabetic and non-diabetic A-FABP knockout mice after MI/R injury, but diminished in wild-type mice. The beneficial effects of A-FABP deficiency on MI/R injury were abolished by the NOS inhibitor N(G)-nitro-L-arginine methyl ester. Thus, A-FABP deficiency protects mice against MI/R-induced and/or diabetes-induced cardiac injury at least partially through activation of the eNOS/NO pathway and reduction in superoxide anion production., (© 2015 Authors; published by Portland Press Limited.)

Obesity is considered to be a chronic inflammatory state in which the dysfunction of adipose tissue plays a central role. The adipokines, which are cytokines secreted by adipose tissue, are key links between obesity and related diseases such as metabolic syndrome and atherosclerosis. LCN2 and A-FABP, both of which are major adipokines predominantly produced in adipose tissue, have recently been shown to be pivotal modulators of vascular function. However, different adipokines modulate the development of atherosclerosis in distinctive manners, which are partly attributable to their unique regulatory mechanisms and functions. This review highlights recent advances in the understanding of the role of two adipokines in mediating chronic inflammation and the pathogenesis of atherosclerosis., (Copyright © 2013 John Wiley & Sons, Ltd.)

Background & Aims: Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non-alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice., Methods: Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR., Results: A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF-κB. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice., Conclusions: These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Experiments were designed to determine the cause of the selective dysfunction of G(i) proteins, characterized by a reduced endothelium-dependent relaxation to serotonin (5-hydroxytryptamine), in coronary arteries lined with regenerated endothelial cells. Part of the endothelium of the left anterior descending coronary artery of female pigs was removed in vivo to induce regeneration. The animals were treated chronically with vehicle (control), apocynin (antioxidant), or BMS309403 (A-FABP inhibitor) for 28 days before functional examination and histological analysis of segments of coronary arteries with native or regenerated endothelium of the same hearts. Isometric tension was recorded in organ chambers and cumulative concentration-relaxation curves obtained in response to endothelium-dependent [serotonin (G(i) protein mediated activation of eNOS) and bradykinin (G(q) protein mediated activation of eNOS)] and independent [detaNONOate (cGMP-mediated), isoproterenol (cAMP-mediated)] vasodilators. The two inhibitors tested did not acutely affect relaxations of preparations with either native or regenerated endothelium. In the chronically treated groups, however, both apocynin and BMS309403 abolished the reduction in relaxation to serotonin in segments covered with regenerated endothelium and prevented the intima-medial thickening caused by endothelial regeneration, without affecting responses to bradykinin or endothelium-independent agonists (detaNONOate and isoproterenol). Thus, inhibition of either oxidative stress or A-FABP likely prevents both the selective dysfunction of G(i) protein mediated relaxation to serotonin and the neointimal thickening resulting from endothelial regeneration.

Background: Obesity is closely associated with various cardiovascular diseases (CVDs). Adipose tissue inflammation and perturbation of adipokine secretion may contribute to the pathogenesis of CVD. This study aimed to evaluate whether the 2 most abundant adipokines, adipocyte-fatty acid binding protein (A-FABP) and adiponectin, are independent risk factors predisposing to CVD., Method and Results: We investigated prospectively the 12-year development of CVD in relation to the baseline levels of A-FABP and adiponectin in a population-based community cohort comprising 1847 Chinese subjects recruited from the Hong Kong Cardiovascular Risk Factors Prevalence Study 2 (CRISPS 2) cohort without previous CVD. Baseline serum levels of A-FABP, adiponectin, and C-reactive protein (CRP), an established biomarker predictive of CVD, were measured. In all, 182 (9.9%) of the 1847 Chinese subjects developed CVD during a median follow-up of 9.4 years. The CVD group had more traditional risk factors, higher baseline levels of A-FABP and CRP (both P<0.001), but similar adiponectin levels (P=0.881) compared with the non-CVD group. In Cox regression analysis including both biomarkers, the adjusted HR for A-FABP and CRP for subjects above the optimal cutoff values were 1.57 (95% CI, 1.14 to 2.16; P=0.006) and 1.60 (95% CI, 1.12 to 2.27; P=0.01), respectively, after adjustment for traditional risk factors. The category-free net reclassification index, but not the c-statistic, showed improvement in predictive performance by the addition of A-FABP to the traditional risk factor model (P=0.017)., Conclusions: Circulating A-FABP level predicts the development of CVD after adjustment for traditional risk factors in a community-based cohort. Its clinical use for CVD prediction warrants further validation.

A-FABP (adipocyte fatty acid-binding protein), one of the most abundant proteins in adipocytes, plays a key role in obesity-related insulin resistance, inflammation and atherosclerosis in animals. In the present study, we sought to investigate the association of A-FABP with HF (heart failure) in Chinese subjects. Serum A-FABP levels were measured in 252 HF patients and 261 age-, gender- and BMI (body mass index)-matched non-HF subjects. Echocardiography was performed on each patient. The severity of HF was determined by the NYHA (New York Heart Association) classification system. After adjustments for age, gender and BMI, serum A-FABP concentrations in patients with HF were significantly higher than in non-HF patients [11.17 (6.63-19.93) ng/ml compared with 5.67 (3.20-8.87) ng/ml; P<0.001] and significantly progressed with the NYHA class (P<0.001). In addition, NT-proBNP (N-terminal pro-brain natriuretic peptide) was independently and positively correlated with A-FABP (standardized β=0.340, P<0.001) after adjusting for confounding factors. Each echocardiographic parameter, especially LVEF (left ventricular ejection fraction), was independently associated with A-FABP (all P<0.05). Multivariate logistic regression analysis demonstrated that A-FABP concentration was an independent risk factor for HF [odds ratio, 6.93 (95% confidence interval, 2.49-19.30); P<0.001]. Our results demonstrate that A-FABP is closely associated with HF, and raise the possibility that increased A-FABP may be causally related to the pathogenesis of heart dysfunction in humans.

The heart and blood vessels are surrounded by epicardial and perivascular adipose tissues, respectively, which play important roles in maintaining cardiovascular homeostasis by secreting a number of biologically active molecules, termed "adipokines." Many of these adipokines function as an important component of the 'adipo-cardiovascular axis' mediating the cross talk between adipose tissues, the heart, and the vasculature. On the one hand, most adipokines [including tumor necrosis factor-α, resistin, adipocyte fatty acid binding protein (A-FABP), and lipocalin-2] are proinflammatory and causally associated with endothelial and cardiac dysfunction by their endocrine/paracrine actions. On the other hand, adiponectin is one of the few adipokines that possesses multiple salutary effects on the prevention of cardiovascular disease, because of its pleiotropic actions on the heart and the blood vessels. The discordant production of adipokines in dysfunctional adipose tissue is a key contributor to obesity-related cardiovascular disease. This review provides an update in understanding the roles of adipokines in the pathogenesis of cardiovascular disorders associated with obesity and diabetes and focuses on the two most abundant adipokines, adiponectin and A-FABP. Indeed, data from both animal studies and clinical investigations imply that these two adipokines are prognostic biomarkers for cardiovascular disease and even promising therapeutic targets for its treatment.

a-FABP is indespensible in inflammation and may serve as a new potential drug target for inflammation related diseases. We have successfully designed and synthesized a series of aromatic substituted pyrazoles as new human a-FABP inhibitors. The compounds strongly bound to the hydrophobic binding pocket of a-FABP, while showed significantly lower binding affinities to the closely related homologue protein h-FABP. The most potent and selective compound 5 g bound to a-FABP with an apparent K(i) value below 1.0 nM, while did not inhibit h-FABP at 50 μM and thus represents one of the most potent and selective a-FABP inhibitors to date. The strong binding capacity of these inhibitors was further validated by their effective blockade of inflammatory responses as determined by the production of pro-inflammatory cytokines upon LPS stimulation. Compound 5 g may serve as a lead compound for developing new effective therapeutic agent for prevention and treatment of atherosclerosis, type 2 diabetes and other inflammatory and metabolic related diseases., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Adipocyte fatty acid-binding protein (A-FABP) has emerged as an important mediator of inflammation in macrophages. Macrophage-selective ablation of A-FABP alone is sufficient to prevent the development of high cholesterol diet-induced atherosclerosis in apoE-deficient mice. However, the precise mechanisms whereby A-FABP modulates inflammation remain elusive. Here, we report that A-FABP forms a finely tuned positive loop between JNK and activator protein-1 (AP-1) to exacerbate lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Real time PCR and luciferase reporter analysis showed that LPS induced A-FABP expression through transcriptional activation. This effect was mediated by JNK, which promoted the recruitment of c-Jun to a highly conserved AP-1 consensus binding motif located within the proximal region of the A-FABP promoter. LPS-induced transactivation of the A-FABP gene was diminished by either pharmacological inhibition of JNK or knocking down c-Jun or by mutating the AP-1 recognition site within the proximal region (-122 to -116 bp) of the A-FABP promoter. Conversely, the LPS-evoked phosphorylation of JNK, activation of AP-1, and production of pro-inflammatory cytokines were markedly attenuated by pharmacological or genetic suppression of A-FABP in macrophages. Furthermore, the LPS-induced elevation in A-FABP expression could also be prevented by the selective A-FABP inhibitor BMS309403. These findings support the notion that pharmacological inhibition of A-FABP represents a valid strategy for treating inflammation-related disorders such as atherosclerosis.

Unlabelled: Several circulating cytokines are increased with obesity and may combine with the influence of visceral fat to generate insulin resistance, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). Little information exists in NAFLD about three recently recognized tissue-derived cytokines that are all lipid-binding and involved in inflammation, namely adipocyte fatty acid-binding protein (AFABP), lipocalin-2, and retinol-binding protein 4 (RBP4). We examined the association of these three peptides with hepatic steatosis, inflammation, and fibrosis plus indices of adiposity, insulin resistance, and dyslipidaemia in 100 subjects with NAFLD and 129 matched controls. Levels of AFABP and lipocalin-2, but not RBP4, were significantly elevated in NAFLD versus control (AFABP, 33.5 +/- 14.4 versus 23.1 +/- 12.1 ng/mL [P < 0.001]; lipocalin-2, 63.2 +/- 26 versus 48.6 +/- 20 ng/mL [P < 0.001]) and correlated with indices of adiposity. AFABP correlated with indices of subcutaneous rather than visceral fat. AFABP alone distinguished steatohepatitis from simple steatosis (P= 0.02). Elevated AFABP independently predicted increasing inflammation and fibrosis, even when insulin resistance and visceral fat were considered; this applied to lobular inflammation and ballooning (odds ratio 1.4, confidence interval 1.0-1.8) and fibrosis stage (odds ratio 1.3, confidence interval 1.0-1.7) (P < or = 0.05 for all). None of the cytokines correlated with steatosis grade. AFABP levels correlated with insulin resistance (homeostasis model assessment of insulin resistance) in controls and NAFLD, whereas lipocalin-2 and RBP4 only correlated positively with insulin resistance in controls., Conclusion: Circulating AFABP, produced by adipocytes and macrophages, and lipocalin-2, produced by multiple tissues, are elevated and may contribute to the metabolic syndrome in NAFLD. AFABP levels, which correlate with subcutaneous, but not visceral fat, independently predict inflammation and fibrosis in NAFLD and may have a direct pathogenic link to disease progression.

Objective: To investigate the relationships of serum adipocyte fatty acid-binding protein (A-FABP) and epidermal fatty acid-binding protein (E-FABP) with renal dysfunction and macrovascular complications in type 2 diabetic patients., Research Design and Methods: The associations of serum A-FABP and E-FABP with markers of renal function, nephropathy staging, and macrovascular complications were examined in 237 type 2 diabetic patients., Results: Serum A-FABP and E-FABP correlated significantly with serum creatinine, mean albumin excretion rate, and glomerular filtration rate (all P < 0.001) and were independently associated with diabetic nephropathy staging (P = 0.001 and P < 0.05, respectively). Circulating levels of both types of FABP were increased (P < 0.01) in subjects with macrovascular complications. Serum A-FABP was independently associated with macrovascular complications (odds ratio 2.92 [95% CI 1.42-6.01]; P = 0.004)., Conclusions: Serum A-FABP and E-FABP might be novel serum biomarkers for evaluating the progression of nephropathy and its cardiovascular risk in type 2 diabetic patients.

Aims: Epidermal fatty-acid-binding protein (E-FABP) is highly homologous to adipocyte FABP (A-FABP), which mediates obesity-related metabolic syndrome (MetS), diabetes and atherosclerosis in animals. Combined deficiency of E-FABP and A-FABP protects against the MetS and atherosclerosis in mice. This study investigated the association of serum E-FABP with cardio-metabolic risk factors and carotid atherosclerosis in humans., Methods and Results: The presence of E-FABP in human plasma was detected by tandem mass spectrometry. Serum E-FABP levels, determined by an enzyme-linked immunosorbent assay in 479 Chinese subjects (age: 55.4 ± 13.5 years; M/F: 232/247), correlated positively (P < 0.05 to <0.001, age-adjusted) with parameters of adiposity, adverse lipid profiles, serum insulin, A-FABP, and C-reactive protein levels and were higher in subjects with the MetS (P < 0.001 vs. no MetS). The association of E-FABP with the MetS was independent of A-FABP. Furthermore, serum E-FABP correlated with carotid intima-media thickness (IMT; P < 0.001) and was independently associated with carotid IMT in men (adjusted P = 0.03)., Conclusion: E-FABP is a new circulating biomarker associated with increased cardio-metabolic risk. It may contribute to the development of the MetS and carotid atherosclerosis in humans, independent of the effect of A-FABP.

Objective: Adipocyte fatty acid-binding protein (A-FABP) is abundantly expressed in adipocytes and plays a role in glucose homeostasis in experimental animals. We have previously shown that circulating A-FABP levels are associated with the metabolic syndrome, which confers an increased risk of type 2 diabetes. Here we investigated whether serum A-FABP levels could predict the development of diabetes in a 10-year prospective study., Research Design and Methods: Baseline serum A-FABP levels were measured with an enzyme-linked immunosorbent assay in 544 nondiabetic subjects, recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort, who were followed prospectively to assess the development of type 2 diabetes. The role of A-FABP in predicting the development of type 2 diabetes over 10 years was investigated using Cox regression analysis., Results: At baseline, serum sex-adjusted A-FABP levels were higher in subjects with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) (P < 0.00001 versus normal glucose tolerance) and correlated positively with adverse cardiometabolic risk factors. Over 10 years, 96 subjects had developed type 2 diabetes. High baseline A-FABP was predictive of type 2 diabetes, independent of obesity, insulin resistance, or glycemic indexes (relative risk [RR] 2.25 [95% CI 1.40-3.65]; P = 0.001; above versus below sex-specific median). High A-FABP levels remained an independent predictor of type 2 diabetes in the high-risk IGT/IFG subgroup (adjusted RR 1.87 [1.12-3.15]; P = 0.018)., Conclusions: Serum A-FABP was associated with glucose dysregulation and predicted the development of type 2 diabetes in a Chinese cohort.

Background: Adipocyte-fatty acid binding protein (A-FABP), a major cytoplasmic protein in adipocytes, plays a central role in the development of diabetes and atherosclerotic cardiovascular disease in experimental animals. We have previously shown that A-FABP is present in the bloodstream and that its circulating levels correlate with metabolic risk factors in a cross-sectional study. In the present study, we further evaluated the prospective association of A-FABP with the metabolic syndrome (MetS) as defined by the updated National Cholesterol Education Program criteria., Methods and Results: In the present study, 495 nondiabetic adults from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study were prospectively followed up for 5 years. The relationship of serum A-FABP with the MetS and its components was investigated. At baseline, high A-FABP levels were associated with the MetS (odds ratio, 4.0; 95% CI, 1.5 to 10.4; highest versus lowest sex-specific tertile, adjusted for age, body mass index, the homeostasis model assessment index for insulin resistance, C-reactive protein, and adiponectin, P=0.005). On long-term follow-up, subjects with higher baseline A-FABP levels had progressively worse cardiometabolic risk profile and increasing risk of the MetS. Among 376 subjects without the MetS at baseline, 50 had developed it at 5 years. Apart from the homeostasis model assessment index for insulin resistance (P=0.001), baseline A-FABP was the only independent predictor of the development of the MetS during the 5-year follow-up (odds ratio, 4.7; 95% CI, 1.8 to 11.9; highest versus lowest sex-specific tertile, P=0.001, adjusted for the homeostasis model assessment index for insulin resistance and body mass index). A-FABP was predictive of the MetS even after adjustment for each of its individual components., Conclusions: Circulating A-FABP predicts the development of the MetS independently of adiposity and insulin resistance.

Background: Adipocyte fatty acid-binding protein (A-FABP) is traditionally thought to be a cytosolic fatty acid chaperone expressed in adipocytes. Mice with targeted disruption of the A-FABP gene exhibit a striking phenotype with strong protection from insulin resistance, hyperglycemia, and atherosclerosis. The clinical relevance of these findings remains to be confirmed., Methods: We used tandem mass spectrometry-based proteomic analysis to identify proteins secreted from adipocytes and present in human serum. We measured serum A-FABP concentrations in 229 persons (121 men and 108 women; age range, 33-72 years), including 100 lean [body mass index (BMI) <25 kg/m2] and 129 overweight/obese individuals (BMI >25 kg/m2) selected from a previous cross-sectional study., Results: A-FABP was released from adipocytes and was abundantly present in human serum. Mean (SD) circulating concentrations of A-FABP were significantly higher in overweight/obese than in lean persons [32.3 (14.8) vs 20.0 (9.8) microg/L; P < 0.001]. Age- and sex-adjusted serum A-FABP concentrations correlated positively (P < 0.005) with waist circumference, blood pressure, dyslipidemia, fasting insulin, and the homeostasis model assessment insulin resistance index. Moreover, we observed a significant increase in A-FABP concentrations corresponding with increases in the number of components of the metabolic syndrome (P < 0.05)., Conclusions: A-FABP is a circulating biomarker closely associated with obesity and components of the metabolic syndrome, and measurement of serum concentrations of A-FABP might be useful for clinical diagnosis of obesity-related metabolic and cardiovascular disorders.

Background and Purpose: Adipocyte fatty acid‐binding protein (A‐FABP) exacerbates cerebral ischaemia injury by disrupting the blood–brain barrier (BBB) through inducing expression of MMP‐9. Circulating A‐FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A‐FABP by a neutralizing antibody would alleviate ischaemic stroke outcome. Experimental Approach: Monoclonal antibodies (mAbs) against A‐FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2‐A‐FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively. Key Results: Replenishment of recombinant A‐FABP exaggerated the stroke outcome in A‐FABP‐deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A‐FABP, respectively, with minimal cross‐reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c‐Jun activation elicited by A‐FABP and reduced MMP‐9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A‐FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP‐9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice. Conclusion and Implications: These results establish circulating A‐FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity. [ABSTRACT FROM AUTHOR]

Background & Aims: It is unknown how concomitant hepatic steatosis affects disease progression in chronic hepatitis B (CHB). Adipokines such as fibroblast growth factor 21 (FGF21) and adipocyte fatty acid‐binding protein (AFABP) have been associated with non‐alcoholic fatty liver disease. We determined the significance of these metabolic markers in CHB‐related liver injury. Methods: We recruited CHB patients on antiviral treatment for transient elastography assessment to determine liver stiffness (advanced fibrosis/cirrhosis, F3/F4, defined by EASL‐ALEH criteria) and controlled attenuation parameter (hepatic steatosis, defined as ≥ 248 dB/m). Plasma FGF‐21, AFABP and adiponectin levels were measured. Results: A total of 415 patients [mean age 59.6 years, 71.6% male, median treatment duration 6.2 years] were recruited. Patients with F3/F4 (N = 151) had lower FGF‐21 (11.7 vs 13.6 pg/mL, P = 0.055), higher AFABP (126.8 vs 84.1 pg/mL, P < 0.001) and HOMA‐IR (7.1 vs 5.1, P = 0.004) levels compared to those without F3/F4 (N = 264). Multivariate analysis showed that FGF‐21 level was associated with hepatic steatosis (OR 1.005, 95% CI 1.001‐1.009) and F3/F4 (OR 0.993, 95% CI 0.989‐0.998), while AFABP level (OR 1.001, 95% CI 1‐1.002), body mass index (BMI) (OR 1.107, 95% CI 1.037‐1.182) and presence of diabetes mellitus (OR 2.059, 95% CI 1.206‐3.516) were associated with F3/F4. With the combined presence of BMI ≥ 25 kg/m2, diabetes and AFABP > 105.9 pg/mL, the odds ratio for F3/F4 was 3.712 (95% CI 1.364‐10.105, P = 0.010). Conclusions: Low FGF‐21 and high AFABP levels were associated with advanced fibrosis/cirrhosis in CHB patients on antiviral treatment. Plasma AFABP, together with other metabolic risk factors, may aid identification of patients lacking fibrosis improvement during antiviral treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Adipocyte fatty acid-binding protein (A-FABP) is up-regulated in regenerated endothelial cells and modulates inflammatory responses in macrophages. Endothelial dysfunction accompanying regeneration is accelerated by hyperlipidaemia. Here, we investigate the contribution of A-FABP to the pathogenesis of endothelial dysfunction in the aorta of apolipoprotein E-deficient (ApoE(-/-) ) mice and in cultured human endothelial cells.Experimental Approach: A-FABP was measured in aortae of ApoE(-/-) mice and human endothelial cells by RT-PCR, immunostaining and immunoblotting. Total and phosphorylated forms of endothelial nitric oxide synthase (eNOS) were measured by immunoblotting. Changes in isometric tension were measured in rings of mice aortaeKey Results: A-FABP was expressed in aortic endothelium of ApoE(-/-) mice aged 12 weeks and older, but not at 8 weeks or in C57 wild-type mice. Reduced endothelium-dependent relaxations to acetylcholine, UK14304 (selective α(2) -adrenoceptor agonist) and A23187 (calcium ionophore) and decreased protein presence of phosphorylated and total eNOS were observed in aortae of 18 week-old ApoE(-/-) mice compared with age-matched controls. A 6 week treatment with the A-FABP inhibitor, BMS309403, started in 12 week-old mice, improved endothelial function, phosphorylated and total eNOS and reduced plasma triglyceride levels but did not affect endothelium-independent relaxations. The beneficial effect of BMS309403 on UK14304-induced relaxations was attenuated by Pertussis toxin. In cultured human microvascular endothelial cells, lipid-induced A-FABP expression was associated with reduced phosphorylated eNOS and NO production and was reversed by BMS309403.Conclusions and Implications: Elevated expression of A-FABP in endothelial cells contributes to their dysfunction both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]