Association of selected adipokines with vitamin D deficiency in children with inflammatory bowel disease.

BACKGROUND: Adipose tissue is significantly involved in inflammatory bowel disease (IBD). Vitamin D can affect both adipogenesis and inflammation. The aim of this study was to compare the production of selected adipokines, potentially involved in the pathogenesis of IBD - adiponectin, resistin, retinol binding protein 4 (RBP-4), adipocyte fatty acid binding protein and nesfatin-1 in children with IBD according to the presence of 25-hydroxyvitamin D (25(OH)D) deficiency. METHODS: The study was conducted as a case-control study in pediatric patients with IBD and healthy children of the same sex and age. In addition to adipokines and 25(OH)D, anthropometric parameters, markers of inflammation and disease activity were assessed in all participants. RESULTS: Children with IBD had significantly higher resistin levels regardless of 25(OH)D levels. IBD patients with 25(OH)D deficiency only had significantly lower RBP-4 compared to healthy controls and also compared to IBD patients without 25(OH)D deficiency. No other significant differences in adipokines were found in children with IBD with or without 25(OH)D deficiency. 25(OH)D levels in IBD patients corelated with RBP-4 only, and did not correlate with other adipokines. CONCLUSIONS: Whether the lower RBP-4 levels in the 25(OH)D-deficient group of IBD patients directly reflect vitamin D deficiency remains uncertain. The production of other adipokines does not appear to be directly related to vitamin D deficiency.

Development of a therapeutic monoclonal antibody against circulating adipocyte fatty acid binding protein to treat ischaemic stroke.

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.

Effect of obesity, lipids and adipokines on allergic rhinitis risk: a Mendelian randomization study

Abstract Objectives: Observational studies suggested that obesity may promote the development of allergic rhinitis. The aim of this study was to explore the association of obesity, lipids and adipokines with this allergic disease at the genetic level using Mendelian randomization strategies. Methods: Summary data for three obesity indicators (such as body mass index), eight lipid indicators (such as triglycerides) and six adipokines (such as interleukin-6 and adipocyte fatty acid-binding protein) were collected, and suitable instrumental variables were extracted from these summary data according to the three main assumptions of Mendelian randomization. Three Mendelian randomization methods (such as inverse variance weighted) were used to detect the casual effect of the above indicators on allergic rhinitis risk. Sensitivity analyses were performed to assess heterogeneity and horizontal pleiotropy. Results: After Bonferroni correction, the inverse variance weighted reported that elevated levels of interleukin-6 and adipocyte fatty acid-binding protein were nominally associated with the decreased risk of allergic rhinitis (OR = 0.870, 95% CI 0.765-0.990, p = 0.035; OR = 0.732, 95% CI 0.551-0.973, p = 0.032). The other Mendelian randomization methods supported these results. Obesity, lipids and other adipokines were not related to this allergic disease. Sensitivity analyses found no heterogeneity and horizontal pleiotropy in the study. Conclusion: The study provided some interesting, but not sufficient, evidence to suggest that interleukin-6 and adipocyte fatty acid-binding protein might play a protective role in the development of allergic rhinitis at the genetic level. These findings should be validated by more research. Level of evidence: This was a Mendelian randomized study with a level of evidence second only to clinical randomized trials, and higher than cohort and case-control studies.

Effect of obesity, lipids and adipokines on allergic rhinitis risk: a Mendelian randomization study.

OBJECTIVES: Observational studies suggested that obesity may promote the development of allergic rhinitis. The aim of this study was to explore the association of obesity, lipids and adipokines with this allergic disease at the genetic level using Mendelian randomization strategies. METHODS: Summary data for three obesity indicators (such as body mass index), eight lipid indicators (such as triglycerides) and six adipokines (such as interleukin-6 and adipocyte fatty acid-binding protein) were collected, and suitable instrumental variables were extracted from these summary data according to the three main assumptions of Mendelian randomization. Three Mendelian randomization methods (such as inverse variance weighted) were used to detect the casual effect of the above indicators on allergic rhinitis risk. Sensitivity analyses were performed to assess heterogeneity and horizontal pleiotropy. RESULTS: After Bonferroni correction, the inverse variance weighted reported that elevated levels of interleukin-6 and adipocyte fatty acid-binding protein were nominally associated with the decreased risk of allergic rhinitis (OR = 0.870, 95% CI 0.765-0.990, p = 0.035; OR = 0.732, 95% CI 0.551-0.973, p = 0.032). The other Mendelian randomization methods supported these results. Obesity, lipids and other adipokines were not related to this allergic disease. Sensitivity analyses found no heterogeneity and horizontal pleiotropy in the study. CONCLUSION: The study provided some interesting, but not sufficient, evidence to suggest that interleukin-6 and adipocyte fatty acid-binding protein might play a protective role in the development of allergic rhinitis at the genetic level. These findings should be validated by more research. LEVEL OF EVIDENCE: This was a Mendelian randomized study with a level of evidence second only to clinical randomized trials, and higher than cohort and case-control studies.

Circulating AFABP, FGF21, and PEDF Levels as Prognostic Biomarkers of Sight-threatening Diabetic Retinopathy.

CONTEXT: Adipocyte fatty acid-binding protein (AFABP), fibroblast growth factor 21 (FGF21), and pigment epithelium-derived factor (PEDF) are 3 diabetes-related biomarkers whose circulating levels had been shown to associate with nephropathy progression in Chinese patients with type 2 diabetes. OBJECTIVE: Here, we evaluated and compared their prospective associations with the development of sight-threatening DR (STDR), another important diabetic microvascular complication. METHODS: Baseline serum AFABP, PEDF, and FGF21 levels were measured in 4760 Chinese individuals with type 2 diabetes and without STDR at baseline. The associations of these biomarkers with incident STDR were analyzed using Cox regression analysis. RESULTS: Among these 4760 participants (mean diabetes duration of 11 years and ≥ 50% with nonproliferative DR at baseline), 172 participants developed STDR over a median follow-up of 8.8 years. Participants with incident STDR had comparable baseline serum FGF21 levels but significantly higher baseline serum AFABP and PEDF levels (both P < .001) than those without. However, in multivariable Cox regression analysis, only serum AFABP remained independently associated with incident STDR (hazard ratio 1.28; 95% CI, 1.05-1.55; P = .013). The addition of serum AFABP to a clinical model of conventional STDR risk factors including diabetes duration, glycemic control, albuminuria, and baseline DR status significantly improved the c statistics (P < .001), net reclassification index (P = .0027), and integrated discrimination index (P = .033) in predicting incident STDR among participants without DR or with mild DR at baseline. CONCLUSION: Among the 3 diabetes-related biomarkers, serum AFABP level appeared to be a more clinically useful biomarker for predicting incident STDR in type 2 diabetes.

The Association and Joint Effect of Adipocyte Fatty Acid Binding Protein and Obesity Phenotype With Cardiovascular Events.

CONTEXT: There is little evidence regarding the joint effect of serum adipocyte fatty acid binding protein (A-FABP) levels and obesity phenotype on the risk of cardiovascular events. OBJECTIVE: To explore the association between serum A-FABP levels and obesity phenotype defined by fat percentage (fat%) and visceral fat area (VFA), and their joint impact on incident cardiovascular events. METHODS: A total of 1345 residents (579 men and 766 women) without previous cardiovascular diseases at baseline, with body composition and serum A-FABP data available, were included. A bioelectrical impedance analyzer and magnetic resonance imaging were used to assess fat% and VFA, respectively. RESULTS: During a mean follow-up of 7.6 years, 136 cases of cardiovascular events (13.9 per 1000 person-years) occurred. Per 1-unit increase in loge-transformed A-FABP levels was associated with an increase in cardiovascular events risk (hazard ratio [HR] 1.87, 95% CI 1.33-2.63). The highest tertiles of fat% and VFA levels were related to higher risks of cardiovascular events (fat%: HR 2.38, 95% CI 1.49-3.81; VFA: HR 1.79, 95% CI 1.09-2.93). The association between A-FABP levels and cardiovascular events was more pronounced in participants with low fat%, regardless of VFA levels. The joint effect of high A-FABP levels and obesity resulted in a greater risk of cardiovascular events. CONCLUSION: Serum A-FABP levels were significantly associated with the risk of cardiovascular events, and this pattern of association was more prominent among the population with low fat%, which was independent of VFA.

Conjugated linoleic acid regulates adipocyte fatty acid binding protein expression via peroxisome proliferator-activated receptor α signaling pathway and increases intramuscular fat content.

Intramuscular fat (IMF) is correlated positively with meat tenderness, juiciness and taste that affected sensory meat quality. Conjugated linoleic acid (CLA) has been extensively researched to increase IMF content in animals, however, the regulatory mechanism remains unclear. Adipocyte fatty acid binding protein (A-FABP) gene has been proposed as candidates for IMF accretion. The purpose of this study is to explore the molecular regulatory pathways of CLA on intramuscular fat deposition. Here, our results by cell lines indicated that CLA treatment promoted the expression of A-FABP through activated the transcription factor of peroxisome proliferator-activated receptor α (PPARα). Moreover, in an animal model, we discovered that dietary supplemental with CLA significantly enhanced IMF deposition by up-regulating the mRNA and protein expression of PPARα and A-FABP in the muscle tissues of mice. In addition, our current study also demonstrated that dietary CLA increased mRNA expression of genes and enzymes involved in fatty acid synthesis and lipid metabolism the muscle tissues of mice. These findings suggest that CLA mainly increases the expression of A-FABP through PPARα signaling pathway and regulates the expression of genes and enzymes related to IMF deposition, thus increasing IMF content. These results contribute to better understanding the molecular mechanism of IMF accretion in animals for the improvement of meat quality.

Fatty Acid-Binding Proteins in Psoriasis-A Review.

Psoriasis is one of the most common skin diseases in dermatological practice. It affects about 1-3% of the general population and is associated with different comorbidities, especially metabolic syndrome. Fatty-acid-binding proteins (FABPs) are a family of cytosolic proteins which are an important link in lipid metabolism and transport; moreover, they have different tissue specificity and properties. So far, ten FABPs have been discovered and seven have been investigated in psoriasis. In this review, we discuss the nature of all FABPs and their role in psoriasis. FABPs have different organ and tissue expression, and hence various functions, and may be markers of different disorders. Considering the concentration of a few of them tends to be elevated in psoriasis, it confirms the current perception of psoriasis as a multiorgan disorder associated with plenty of comorbidities. Some FABPs may be also further investigated as biomarkers of psoriasis organ complications. FABP-1 and FABP-5 may become potential markers of metabolic complications and inflammation in psoriasis. FABP-7 could perhaps be further investigated as an indicator of the neurodegenerative processes in psoriatic patients.

Serum Adipocyte Fatty-Acid Binding Protein as an Independent Marker of Peripheral Artery Disease in Patients with Type-2 Diabetes Mellitus.

The adipocyte fatty-acid binding protein (A-FABP) is predominantly expressed in macrophages and adipocytes and is an essential mediator of inflammation and atherosclerosis pathogenesis. Atherosclerosis is an aggravating factor for peripheral arterial disease (PAD). Our study intended to study the association between PAD and serum A-FABP levels in type-2 diabetes mellitus (T2DM) patients. One hundred and twenty T2DM subjects were enrolled in the study. Fasting blood samples were collected to determine biochemical data and A-FABP levels. By the automatic oscillometric method, the ankle−brachial index (ABI) was measured. Low ABI was defined as any value < 0.9. Twenty participants with T2DM (16.7%) were included in the low ABI group. Low ABI T2DM participants had an increased mean body mass index, body fat mass, systolic blood pressure, C-reactive protein, urine albumin−creatinine ratio, and A-FABP levels compared to those in the normal ABI group. After variables significantly associated with PAD were adjusted by multivariate logistic regression analyses, circulating A-FABP levels (odds ratio [OR]: 1.138; 95 percent confidence interval [CI]: 1.023−1.266; p = 0.017) were identified as the independent marker of PAD. In conclusion, fasting serum A-FABP value has positive association with PAD in T2DM patients.

Correlation between adipocyte fatty acid binding protein and glucose dysregulation is closely associated with obesity and metabolic syndrome: A cohort of Han Chinese population from Yunnan plateau.

The present study investigated the correlation of plasma A-FABP with glucose dysregulation under different body mass index (BMI) and metabolic states in a Han Chinese population from Yunnan plateau. We cross-sectionally analyzed data from the China Multi Ethnic Cohort, Yunnan province. Participants were divided into two groups. Group A contained 297 obese individuals with metabolic syndrome (MetS). Group B contained 326 age-, sex-, and region-matched normal BMI subjects without MetS. Glucose dysregulation was defined as elevated fasting plasma glucose (FPG) (FPG ≥ 5.6 mmol/L or current use of oral hypoglycemic agents or insulin). Circulating A-FABP were assayed by ELISA method. Binary and multiple regression analyses were preformed to evaluate the correlation between A-FABP and glucose dysregulation. Plasma A-FABP level was significantly higher in group A compared with group B (p < 0.001). Plasma A-FABP level correlated positively with elevated FPG in group A (r = 0.120, p = 0.039), but negatively with elevated FPG in group B (r = -0.115, p = 0.039). Multiple logistic regression analysis revealed that A-FABP was an independent predictor for elevated FPG in group A (ß, 0.028; 95% CI, 1.001-1.056; p < 0.05), but not in group B (ß, -0.008; 95% CI, 0.882-1.117; p > 0.05). In this study, A-FABP was an independent risk factor for glucose dysregulation in obese individuals with MetS living in the Yunnan plateau, but not for those without obesity and MetS.

Adiponectin, A-FABP and FGF-19 Levels in Women with Early Diagnosed Gestational Diabetes.

Background: Adiponectin, adipocyte fatty acid-binding protein (A-FABP), and fibroblast growth factor-19 (FGF-19) belong to proteins involved in glucose metabolism regulation. The aims of the study were to compare the plasma levels of these proteins in women with early diagnosed gestational diabetes mellitus (GDM) to those in healthy controls and to investigate their changes during pregnancy after early intervention. Methods: The study was undertaken as a case-control study. Early GDM diagnosis was based on repeated fasting plasma glucose ≥5.1 and <7.0 mmol/L during the first trimester of pregnancy and exclusion of overt diabetes. Age-matched controls comprised healthy pregnant and non-pregnant women. In addition to adipokines, clinical parameters and measures of glucose control were assessed. Results: Women with GDM (n = 23) had significantly lower adiponectin and higher A-FABP levels compared to healthy pregnant (n = 29) or non-pregnant (n = 25) controls, while no significant differences in FGF-19 between the groups were found. The therapeutic intervention shifted adiponectin and A-FABP levels in GDM women towards concentrations of healthy pregnant controls. Adipokines were associated with visceral adiposity and glucose control. Conclusion: Women with GDM showed altered adipokine production even in the first trimester of pregnancy. Early therapeutic intervention not only improved glucose control but also normalized impaired adipokine production.

Age and Serum Adipocyte Fatty-Acid-Binding Protein Level Are Associated with Aortic Stiffness in Coronary Artery Bypass Graft Patients.

Old age has been proven to be related to progressed arterial or aortic stiffness. Aortic stiffness is an independent predictor of all-cause and cardiovascular disease mortalities in patients who have undergone coronary artery bypass grafting (CABG) surgery. Higher serum concentrations of adipocyte fatty-acid-binding protein (A-FABP) could be considered a predictor of aortic stiffness in patients with hypertension or diabetes mellitus. This study aims to investigate the relationships between A-FABP and aortic stiffness in patients who have received CABG. A total of 84 CABG patients were enrolled in our study from September 2018 to May 2019. Serum A-FABP levels were determined using a commercial enzyme immunoassay. Carotid−femoral pulse wave velocity (cfPWV) > 10 m/s was defined as aortic stiffness. Of the 84 CABG patients, 28 (33.3%) with aortic stiffness had a higher average age; exhibited higher rates of diabetes; and had higher serum creatinine, C-reactive protein, and A-FABP levels compared to controls. Multivariable logistic regression revealed that serum A-FABP levels (odds ratio (OR) = 1.068, 95% confidence interval (CI) 1.017−1.121, p = 0.008) and age (OR = 1.204, 95% CI 1.067−1.359, p = 0.003) were independent predictors of aortic stiffness. Multivariable stepwise linear regression revealed significant positive correlations of age and A-FABP levels with cfPWV values. Serum A-FABP level is positively correlated with cfPWV values, and a high serum A-FABP level is associated with aortic stiffness in patients who have undergone CABG.

Association between Serum Adipocyte Fatty Acid Binding Protein Level and Endothelial Dysfunction in Chronic Hemodialysis Patients.

Adipocyte fatty acid binding protein (A-FABP) is associated with atherosclerosis, and endothelial dysfunction is one of the reasons for adverse cardiovascular outcomes in patients undergoing hemodialysis (HD). This study investigated the correlation between serum A-FABP levels and endothelial function in HD patients. Fasting blood samples were collected from 90 HD patients. A-FABP levels were measured using a commercial enzyme immunoassay kit. Endothelial function was evaluated by a digital thermal monitoring test to measure vascular reactivity index (VRI). VRI < 1.0, 1.0 ≤ VRI < 2.0, and VRI ≥ 2.0 indicated poor, intermediate, and good vascular reactivity, respectively. In total, 14 (15.6%), 38 (42.2%), and 38 (42.2%) HD patients had poor, intermediate, and good VRI, respectively. Patients with poor VRI had lower pre-HD and post-HD body weight, body mass index, and serum creatinine level but higher serum A-FABP level (p = 0.001) than those with intermediate and good VRI. Log-transformed VRI (log-VRI) positively correlated with serum creatinine and negatively correlated with A-FABP by multivariate linear regression analysis. We concluded that A-FABP correlated with endothelial dysfunction in chronic HD patients.

Correlation of serum FABP4 and PPAR γ levels with nonalcoholic fatty liver disease and type 2 diabetes mellitus / 中华内分泌外科杂志

Objective:To explore the correlation between serum adipocyte fatty acid binding protein 4 (FABP4) and peroxisome proliferator activated receptor gamma (PPAR gamma) levels and metabolism related fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM) .Methods:230 patients with T2DM and MAFLD in Zhangjiakou First Hospital from Feb. 2019 to Feb. 2021 were selected. According to their disease conditions, 80 patients with T2DM and without MAFLD were set as simple T2DM group, 78 patients with MAFLD and normal glucose tolerance were set as simple MAFLD group, 72 patients with T2DM and MAFLD were set as T2DM and MAFLD group, and 100 healthy volunteers in the same period were selected as the control group.Results:The levels of HOMA-IR and FABP4 in T2DM patients were significantly higher than those in the control group ( P<0.05) , while the levels of HDL-C, crea and PPAR γ in T2DM grou were significantly lower than those in the control group ( P<0.05) . The levels of BMI, AST, alt, GGT, TG, HOMA-IR and FABP4 in MAFLD group were significantly higher than those in control group ( P<0.05) , while the level of PPAR γ in MAFLD group was significantly lower than that in control group ( P<0.05) . BMI, AST, alt, GGT, TG, HOMA-IR and FABP4 of T2DM patients with MAFLD were significantly higher than those of T2DM patients without MAFLD and control group ( P<0.05) , while HDL-C and PPAR γ were significantly lower than those of T2DM patients without MAFLD and control group ( P<0.05) . HOMA-IR and FABP4 in T2DM patients with MAFLD were significantly higher than those in MAFLD group ( P<0.05) , while HDL-C, crea and PPAR γ were significantly lower than those in MAFLD group ( P<0.05) . FABP4 was positively correlated with HOMA-IR and CREA (all P<0.05) , and negatively correlated with HDL-Cand PPAR γ (all P<0.05) . PPAR γ was positively correlated with TG and ALT (all P<0.05) , and negatively correlated with HOMA-IR ( P<0.05) . Alt, TG, HOMA-IR, FABP4 and PPAR γ were independent risk factors for MAFLD in T2DM patients ( P<0.05) . Conclusion:FABP4 is positively correlated with the occurrence of T2DM and MAFLD, PPAR γ is negatively correlated with the occurrence of T2DM and MAFLD, the negative feedback loop regulation of FABP4 and PPAR γ can cause the occurrence of insulin resistance, so as to improve the risk of T2DM combined with MAFLD, and provide clinical basis for clinical disease prevention and treatment.

Prospective association of serum adipocyte fatty acid-binding protein with heart failure hospitalization in diabetes.

AIMS: Adipocyte fatty acid-binding protein (AFABP) is associated with cardiovascular diseases in type 2 diabetes. Whether circulating AFABP levels are associated with the risk of heart failure (HF) in type 2 diabetes remains undefined. We investigated the prospective association of circulating AFABP levels with incident HF hospitalization in type 2 diabetes, and its relationship to the use of sodium glucose co-transporter 2 inhibitors (SGLT2i) which reduce HF risk. METHODS AND RESULTS: Baseline serum AFABP level was measured in 3322 Chinese participants without known history of cardiovascular diseases or hospitalization for HF, recruited from the Hong Kong West Diabetes Registry. Its association with incident HF hospitalization was evaluated using multivariable Cox regression analysis. Use of SGLT2i was included as a time-dependent covariate. Among these 3322 participants (52.9% men; mean age 60.0 ± 12.6), 176 (5.3%) developed HF hospitalization over a median follow-up of 8 years. Seven hundred and thirty-one (22%) were started on SGLT2i during the study period (empagliflozin 55.1%, dapagliflozin 44.2%, canagliflozin 0.4%, and ertugliflozin 0.3%). Serum AFABP levels were significantly higher in participants who developed HF hospitalization than those who did not (men: 14.8 vs. 8.3 ng/mL; women: 21.5 vs. 14.6 ng/mL; all: 18.6 vs. 10.9 ng/mL, P < 0.001). In multivariable Cox regression analysis, baseline serum AFABP level was significantly associated with incident HF hospitalization [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.06-1.80, P = 0.019] independent of the use of SGLT2i, in a model also consisting of age; sex; body mass index; smoking status; duration of diabetes; hypertension, dyslipidaemia; atrial fibrillation; presence of chronic kidney disease and albuminuria; glycated haemoglobin and high-sensitivity C-reactive protein levels; and use of metformin, insulin, aspirin, furosemide, and beta-blockers at baseline. High cumulative defined daily dose (cDDD) of SGLT2i was protective of incident HF hospitalization (HR 0.10, 95% CI 0.01-0.68, P = 0.019). The addition of circulating AFABP level to a clinical model of conventional HF risk factors provided significant improvement in the category-free net reclassification index (11.5%, 95% CI 1.6-22.1, P = 0.02) and integrated discrimination improvement (0.3%, 95% CI 0.1-1.7, P = 0.04). A dose-dependent reduction in cumulative incidence of HF hospitalization in response to SGLT2i, based on cDDD, was more clearly observed in participants with a higher baseline AFABP level above the sex-specific median (P for trend <0.01). CONCLUSIONS: Circulating AFABP level is independently associated with incident HF hospitalization in type 2 diabetes and is potentially helpful in risk stratification for the prevention of HF hospitalization.

Adipocyte Fatty Acid-Binding Protein, Cardiovascular Diseases and Mortality.

It has been increasingly recognized that inflammation plays an important role in the pathogenesis of cardiovascular disease (CVD). In obesity, adipose tissue inflammation, especially in the visceral fat depots, contributes to systemic inflammation and promotes the development of atherosclerosis. Adipocyte fatty acid-binding protein (AFABP), a lipid chaperone abundantly secreted from the adipocytes and macrophages, is one of the key players mediating this adipose-vascular cross-talk, in part via its interaction with c-Jun NH2-terminal kinase (JNK) and activator protein-1 (AP-1) to form a positive feedback loop, and perpetuate inflammatory responses. In mice, selective JNK inactivation in the adipose tissue significantly reduced the expression of AFABP in their adipose tissue, as well as circulating AFABP levels. Importantly, fat transplant experiments showed that adipose-specific JNK inactivation in the visceral fat was sufficient to protect mice with apoE deficiency from atherosclerosis, with the beneficial effects attenuated by the continuous infusion of recombinant AFABP, supporting the role of AFABP as the link between visceral fat inflammation and atherosclerosis. In humans, raised circulating AFABP levels are associated with incident metabolic syndrome, type 2 diabetes and CVD, as well as non-alcoholic steatohepatitis, diabetic nephropathy and adverse renal outcomes, all being conditions closely related to inflammation and enhanced CV mortality. Collectively, these clinical data have provided support to AFABP as an important adipokine linking obesity, inflammation and CVD. This review will discuss recent findings on the role of AFABP in CVD and mortality, the possible underlying mechanisms, and pharmacological inhibition of AFABP as a potential strategy to combat CVD.

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.

Associations between High Serum Adipocyte Fatty Acid Binding Protein and First Hospitalization in Kidney Transplantation Patients: A 5-Year Follow-up Study.

Adipocyte fatty acid binding protein (A-FABP) is predictive of type 2 diabetes mellitus incidences and metabolic syndrome and is independently associated with atherosclerosis. The present study aimed to assess the association between serum A-FABP levels and future first hospitalization events in kidney transplantation (KT). We enrolled 72 KT patients from January through April 2012 and followed up on these subjects until June 2017. The first hospitalization events incidence was the primary endpoint. Using a commercially available enzyme immunoassay, serum A-FABP levels were measured from the patient's fasting blood samples. During a median 65-month follow-up, 49 first hospitalization events occurred. KT patients with first hospitalization events had greater incidences of hypertension, diabetes, and higher serum blood urea nitrogen, creatinine, triglyceride, and A-FABP levels than those without the events. Kaplan-Meier analysis showed that the cumulative incidence of first hospitalization events was greater in the high A-FABP group than in the low A-FABP group. Multivariate Cox analysis with significant variables showed that serum A-FABP (hazard ratio = 1.012; 95% confidence interval = 1.000-1.025; p = 0.044) was independently associated with first hospitalization events among KT patients. The results revealed that serum A-FABP is associated with first hospitalization events in KT patients. However, further prospective studies are needed to determine the mechanisms underlying this association.

Relationships of adipocyte-fatty acid binding protein and lipocalin 2 with risk factors and chronic complications in type 2 diabetes and effects of fenofibrate: A fenofibrate Intervention and event lowering in diabetes sub-study.

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.

Increased Serum Adipocyte Fatty Acid-Binding Protein Levels Are Associated with Decreased Sensitivity to Thyroid Hormones in the Euthyroid Population.

Background: Serum adipocyte fatty acid-binding protein (A-FABP) and thyroid hormones are closely associated with metabolic disorders; however, their relationship remains unknown. We aimed at investigating the associations of serum A-FABP levels with single and composite indices of the thyroid system. Methods: The study included 1057 community-based euthyroid participants (age range: 27-81 years) in Shanghai, among whom 601 were women. Serum free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) were measured by electrochemical luminescence immunoassay. The thyroid feedback quantile-based index (TFQI), thyrotropin index (TSHI), and thyrotroph thyroxine resistance index (TT4RI) were calculated to evaluate central sensitivity to thyroid hormones. Peripheral sensitivity to thyroid hormones was evaluated by the fT3 to fT4 ratio (fT3/fT4). Enzyme-linked immunosorbent assay was used to measure serum A-FABP levels. Results: Serum A-FABP levels were 6.41 [95% confidence interval: 6.10-6.74] ng/mL among all subjects. Multiple cardiovascular metabolic risk factors were adjusted in the multivariate linear regression analysis and the multinomial logistic regression analysis (nonordinal). In both sexes, serum A-FABP levels were positively associated with fT4 (men: standardized ß = 0.150, p = 0.001; women: standardized ß = 0.218, p < 0.001), TFQI (men: standardized ß = 0.119, p = 0.009; women: standardized ß = 0.165, p < 0.001), and TSHI (men: standardized ß = 0.108, p = 0.017; women: standardized ß = 0.114, p = 0.005); while they were negatively associated with fT3/fT4 (men: standardized ß = -0.122, p = 0.008; women: standardized ß = -0.129, p = 0.001). Serum A-FABP levels were not associated with fT3, TSH, or TT4RI. Compared with the first quartile group of TFQI, for every 10 ng/mL increase in A-FABP, the odds ratio (OR) for the third quartile group of TFQI was 2.213 in women (p = 0.035); the ORs for the fourth quartile group of TFQI were 2.614 in men (p = 0.022) and 3.425 in women (p = 0.002). Conclusions: In a euthyroid population, increased serum A-FABP levels were associated with decreased sensitivity to thyroid hormones, suggesting that A-FABP may mediate the "cross-talk" between adipose tissue and the thyroid system.