Circulating FABP4 Levels Research Articles

Circulating FABP-4 Levels in Patients with Atherosclerosis or Coronary Artery Disease: A Comprehensive Systematic Review and Meta-Analysis.

Cardiovascular diseases (CDs), notably coronary artery disease (CAD) due to atherosclerosis, impose substantial global health and economic burdens. Fatty acid-binding proteins (FABPs), including FABP-4, have been recently linked to CDs. This study conducted a systematic review and meta-analysis to examine FABP-4 levels in CAD and atherosclerosis patients, exploring their potential links to these conditions. A systematic review and meta-analysis were done based on the PRISMA guideline. The international databases including Medline, Embase, Cochrane Library, Scopus, Web of Science, and UpToDate were searched to find all related studies on the effect of FABP-4 on patients with CAD or atherosclerosis which were published till June 2022 without language restriction. The Cochran's Q-test and I2 statistic were applied to assess heterogeneity, a random effect model was used to estimate the pooled standardized mean difference (SMD), a metaregression method was utilized to investigate the factors affecting heterogeneity between studies, and Egger's test was used to assess the publication bias. Of 1051 studies, 9 studies with a sample size of 2327 were included in the systematic review and meta-analysis. The level of circulating FABP-4 in the patient groups was significantly higher than in the control groups (SMD = 0.60 (95% CI: 0.30 to 0.91, I2: 91.47%)). The SMD in female and male patients were 0.26 (95% CI: 0.01 to 0.52, I2: 0%) and 0.22 (95% CI: 0.08 to 0.35, I2: 44.7%), respectively. There was considerable heterogeneity between the studies. The countries had a positive relationship with heterogeneity (coefficient = 0.29, p < 0.001); but BMI, lipid indices, gender, study design, and type of kit had no effect on the heterogeneity. No publication bias was observed (p: 0.137). In summary, this meta-analysis revealed elevated circulating FABP-4 levels in CDs, suggesting its potential as a biomarker for these conditions. Further research is warranted to explore its clinical relevance.

1333-P: The Adipokine Fatty Acid Binding Protein 4 Promotes Glucose Production in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is characterized by maternal hyperglycemia and insulin resistance that develops during pregnancy. Altered secretion of adipokines that modulate insulin action during pregnancy has been implicated in GDM pathogenesis. FABP4 is an adipokine with an important role in promoting insulin resistance in various animal models. In humans, FABP4 was suggested to regulate systemic metabolism. Although elevated levels of circulating FABP4 were demonstrated in GDM, its differential contribution to GDM pathophysiology is unclear. In this study, we aimed to determine the tissue source of elevated circulating FABP4 levels and to assess FABP4 differential contribution in promoting hepatic glucose production in GDM. We included 71 pregnant women defined as normal glucose tolerant (NGT) and 31 diagnosed with GDM. Maternal level of FABP4 before delivery was measured using ELISA. FABP4 circulating levels were increased in GDM compared to NGT (14.1 IQR: 11.5-21.4 ng/ml vs.10.3 IQR: 6.6-12.4 ng/ml, respectively, p=0.0014), with a rapid post-partum decline in FABP4 levels observed in both groups. Using biopsies of placenta, sub-cutaneous (sWAT) and visceral (vWAT) adipose tissues, we observed that FABP4 is secreted from these tissues during pregnancy. FABP4 secretion from vWAT of GDM women was ? 2 fold higher than that of NGT women. Depletion of FABP4 from vWAT conditioned media of NGT or GDM women using monoclonal antibodies, significantly suppressed glucose production in primary hepatocytes by ? 20% and ? 36%, respectively (p&amp;lt;0.05). Taken together, our data highlight the importance of FABP4 in the pathophysiology of enhanced hepatic glucose production in GDM. Disclosure R. Madah: None. I. Ron Ronen: None. M. Rathaus: None. R. Zemet: None. S. Amazaki Tovi: None. A. Tirosh: Advisory Panel; Self; Abbott, AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; DreaMed Diabetes. Research Support; Self; Medtronic. Funding Israeli Diabetes Association

Altered fatty acid‐binding protein 4 (FABP4) expression and function in human and animal models of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality. Risk factors for developing HCC include viral hepatitis, alcohol and obesity. Fatty acid-binding proteins (FABPs) bind long-chain free fatty acids (FFAs) and are expressed in a tissue-specific pattern; FABP1 being the predominant hepatic form, and FABP4 the predominant adipocyte form. The aims of this study were to investigate the expression and function of FABPs1-9 in human and animal models of obesity-related HCC. FABP1-9 expression was determined in a mouse model of obesity-promoted HCC. Based on these data, expression and function of FABP4 was determined in human HCC cells (HepG2 and HuH7) in vitro. Serum from patients with different underlying hepatic pathologies was analysed for circulating FABP4 levels. Livers from obese mice, independent of tumour status, exhibited increased FABP4 mRNA and protein expression concomitant with elevated serum FABP4. In vitro, FABP4 expression was induced in human HCC cells by FFA treatment, and led to FABP4 release into culture medium. Treatment of HCC cells with exogenous FABP4 significantly increased proliferation and migration of human HCC cells. Patient serum analysis demonstrated significantly increased FABP4 in those with underlying liver disease, particularly non-alcoholic fatty liver disease (NAFLD) and HCC. These data suggest FABP4, an FABP not normally expressed in the liver, can be synthesized and secreted by hepatocytes and HCC cells, and that FABP4 may play a role in regulating tumour progression in the underlying setting of obesity.

Exogenous FABP4 induces endoplasmic reticulum stress in HepG2 liver cells

Background and aimsFatty acid binding protein 4 (FABP4) is an intracellular fatty acid (FA) carrier protein that is, in part, secreted into circulation. Circulating FABP4 levels are increased in obesity, diabetes and other insulin resistance (IR) diseases. FAs contribute to IR by promoting endoplasmic reticulum stress (ER stress) and altering the insulin signaling pathway. The effect of FABP4 on ER stress in the liver is not known. The aim of this study was to investigate whether exogenous FABP4 (eFABP4) is involved in the lipid-induced ER stress in the liver. MethodsHepG2 cells were cultured with eFABP4 (40 ng/ml) with or without linoleic acid (LA, 200 μM) for 18 h. The expression of ER stress-related markers was determined by Western blotting (ATF6, EIF2α, IRE1 and ubiquitin) and real-time PCR (ATF6, CHOP, EIF2α and IRE1). Apoptosis was studied by flow cytometry using Annexin V-FITC and propidium iodide staining. ResultseFABP4 increased the ER stress markers ATF6 and IRE1 in HepG2 cells. This effect led to insulin resistance mediated by changes in AKT and JNK phosphorylation. Furthermore, eFABP4 significantly induced both apoptosis, as assessed by flow cytometry, and CHOP expression, without affecting necrosis and ubiquitination. The presence of LA increased the ER stress response induced by eFABP4. ConclusionseFABP4, per se, induces ER stress and potentiates the effect of LA in HepG2 cells, suggesting that FABP4 could be a link between obesity-associated metabolic abnormalities and hepatic IR mechanisms.

FABP4 plasma concentrations are determined by acquired metabolic derangements rather than genetic determinants

Background and aimsCirculating FABP4 is strongly associated with metabolic and cardiovascular risk (CVR) and has been proposed as a new risk biomarker. Several FABP4 gene polymorphisms have been associated with protein expression in vitro and metabolic and vascular alterations in vivo. The aim of this study is to evaluate the impact of FABP4 polymorphisms on FABP4 plasma levels and subclinical arteriosclerosis in patients with obesity, metabolic syndrome (MS) or type 2 diabetes (T2DM). Methods and resultsWe studied 440 individuals with obesity, MS, T2DM or other cardiovascular risk conditions who attended the vascular medicine and metabolism unit of our hospital. Anamnesis, physical examination and anthropometry data were recorded. Standard biochemical parameters were determined. Plasma FABP4 concentrations were measured. Carotid intima-media thickness (cIMT) was assessed using ultrasonography. The following FABP4 gene single-nucleotide polymorphisms (SNPs) were analyzed: rs3834363, rs16909233, rs1054135, rs77878271, rs10808846 and rs8192688. None of the studied gene allele variants were hyper-represented in patients grouped according the presence of metabolic alterations nor were they associated with the FABP4 concentration. The FABP4 gene variants did not determine cIMT differences between the groups. In a multivariate analysis, gender and BMI, but not gene variants, significantly determined plasma FABP4 concentrations. ConclusionsIn clinical settings, the circulating FABP4 levels are determined by the acquired metabolic derangements and not genetic variation.

Fabp4, a new player in the adipo-pancreatic axis.

Fabp4, a new player in the adipo-pancreatic axis.

Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity.

A critical feature of obesity is enhanced insulin secretion from pancreatic β-cells, enabling the majority of individuals to maintain glycaemic control despite adiposity and insulin resistance. Surprisingly, the factors coordinating this adaptive β-cell response with adiposity have not been delineated. Here we show that fatty acid binding protein 4 (FABP4/aP2) is an adipokine released from adipocytes under obesogenic conditions, such as hypoxia, to augment insulin secretion. The insulinotropic action of FABP4 was identified using an in vitro system that recapitulates adipocyte to β-cell endocrine signalling, with glucose-stimulated insulin secretion (GSIS) as a functional readout, coupled with quantitative proteomics. Exogenous FABP4 potentiated GSIS in vitro and in vivo, and circulating FABP4 levels correlated with GSIS in humans. Insulin inhibited FABP4 release from adipocytes in vitro, in mice and in humans, consistent with feedback regulation. These data suggest that FABP4 and insulin form an endocrine loop coordinating the β-cell response to obesity.

Short term resistance training enhanced plasma apoA-I and FABP4 levels in Streptozotocin-induced diabetic rats

BackgroundType 1 diabetes mellitus is associated with a high risk for early atherosclerotic complications. Altered lipids and lipoprotein metabolism in chronic diabetes mellitus is associated with pathogenesis of atherosclerosis and other cardiovascular diseases. The aim of this study was to investigate the effects of 4 weeks resistance training on plasma lipid profile, fatty acid binding protein (FABP) 4 and apolipoprotein (apo) A-I levels in type 1 diabetic rats.MethodsThirty two male Wister rats (12–14 weeks old) were randomly divided into four groups: non-diabetic control; non-diabetic trained; diabetic control; diabetic trained. The rats in training groups were subjected to a resistance training program (3 days/wk, for 4 wk) consisted of climbing a ladder carrying a load suspended from the tail.ResultsDiabetic inducing increased plasma apoA-I and decreased FABP4 levels compared with non-diabetic control group (respectively, P = 0.001 & P = 0.041). After 4 weeks’ resistance training, plasma levels of apoA-I and FABP4 in the diabetic trained rats were significantly higher compared with the diabetic control group (respectively, P = 0.003 & P = 0.017). Plasma HDL-C level in diabetic trained group was higher than diabetic control group (P = 0.048). Liver triglycerides concentrations were significantly lower in both trained (non-diabetic and diabetic) groups compared with their control groups (respectively, P = 0.041 and P = 0.002).ConclusionThese data indicated that resistance training may be an efficient intervention strategy to increase plasma apoA-I, HDL-C and FABP4 concentrations, along with decreases liver triglycerides in streptozotocin induced diabetic rats. Further research is needed to elucidate physiological significance of circulating FABP4 levels.

Circulating FABP4 and subclinical atherosclerosis in obstructive sleep apnea syndrome

Introduction Obstructive sleep apnea (OSA) is associated with high cardiovascular risk. Carotid intimae media thickness (cIMT) is a surrogate marker of subclinical atherosclerosis. Circulating adipocyte fatty acid-binding protein (FABP4) levels have been associated with metabolic alterations and increased cardiovascular morbidity. Our aim was to evaluate circulating FABP4 concentrations and cIMT in OSA patients. Materials and methods We included 125 participants, aged 18–75, referred by suspected OSA to our Sleep Disorders Unit. OSA was assessed by overnight polysomnography (PSG). Circulating FABP4 levels were determined by ELISA and cIMT was measured by ultrasonography. Results Circulating FABP4 levels were higher in the presence of OSA (25.8 ± 9.7 vs. 19.1 ± 7.9 μ g/l, p = 0.003) and according to OSA severity (overall p = 0.017). The presence of atheromatous carotid plaque as well as cIMT mean values were both higher in OSA compared to non OSA participants (48% vs. 2%, p = 0.004 and 665.4 ± 120.1 vs. 581.3 ± 78.1 μ m, p = 0.005, respectively). cIMT did not differ between OSA severity groups. Moreover, FABP4 levels were positively correlated with cIMT (r = 0.341, p 0.001). Conclusion FABP4 is associated to OSA presence and severity. FABP4 is a biomarker of metabolic comorbidities in OSA patients. The carotid ultrasonography in these patients can reliably report of the precociousness of arteriosclerotic phenomenon. However, more studies are needed before this technique is widespread in our sleep units. Acknowledgements SOCAP, SEPAR and CIBERDEM.

Common FABP4 Genetic Variants and Plasma Levels of Fatty Acid Binding Protein 4 in Older Adults

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p≤0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p=0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency=16%; p=0.001) and African Americans (frequency=8%; p=0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

Tamoxifen inhibits macrophage FABP4 expression through the combined effects of the GR and PPARγ pathways

Macrophage adipocyte fatty acid-binding protein (FABP4) plays an important role in foam cell formation and development of atherosclerosis. Tamoxifen inhibits this disease process. In the present study, we determined whether the anti-atherogenic property of tamoxifen was related to its inhibition of macrophage FABP4 expression. We initially observed that tamoxifen inhibited macrophage/foam cell formation, but the inhibition was attenuated when FABP4 expression was selectively inhibited by siRNA.We then observed that tamoxifen and 4-hydroxytamoxifen inhibited FABP4 protein expression in primary macrophages isolated from both the male and female wild-type mice, suggesting that the inhibition is sex-independent. Tamoxifen and 4-hydroxytamoxifen inhibited macrophage FABP4 protein expression induced either by activation of GR (glucocorticoid receptor) or PPARγ (peroxisome-proliferator-activated receptor γ). Associated with the decreased protein expression, Fabp4 mRNA expression and promoter activity were also inhibited by tamoxifen and 4-hydroxytamoxifen, indicating transcriptional regulation. Analysis of promoter activity and EMSA/ChIP assays indicated that tamoxifen and 4-hydroxytamoxifen activated the nGRE (negative glucocorticoid regulatory element), but inhibited the PPRE (PPARγ regulatory element) in the Fabp4 gene. In vivo, administration of tamoxifen to ApoE (apolipoprotein E)-deficient (apoE-/-) mice on a high-fat diet decreased FABP4 expression in macrophages and adipose tissues as well as circulating FABP4 levels. Tamoxifen also inhibited FABP4 protein expression by human blood monocyte-derived macrophages. Taken together, the results of the present study show that tamoxifen inhibited FABP4 expression through the combined effects of GR and PPARγ signalling pathways. Our findings suggest that the inhibition of macrophage FABP4 expression can be attributed to the antiatherogenic properties of tamoxifen.

SERUM FATTY ACID BINDING PROTEIN 4 IS AN EARLY MARKER FOR ACUTE MYOCARDIAL INFARCTION

Fatty acid binding protein 4 (FABP4, also designated as adipocyte-FABP or aP2) has been described to be most exclusively expressed in adipocytes and macrophages. Circulating FABP4 levels have been linked to metabolic alternations that are associated adiposity. We have recently reported that FABP4 is

FABP4, función endotelial y grosor de la íntima-media carotídeo en pacientes con riesgo cardiovascular

Objective Adipocyte fatty acid binding protein (FABP4) plasma levels are higher in type 2 diabetes (T2D), obesity and metabolic syndrome. Endothelial dysfunction is a common feature in the development of vascular diseases associated with metabolic disturbances. We have investigated the relationship between circulating FABP4 levels and endothelial function in patients at cardiovascular risk. Methods Two hundred and fifty-seven patients (mean age, 57.29 ± 10.66 years) at increased cardiovascular risk (CVR). Fasting plasma FABP4 levels were measured. Endothelial function was assessed as reactive hyperemia (IHR) by peripheral artery tonometry (PAT), carotid intima-media thickness and ankel-brachial index. Antropometry and endothelial, inflammation and oxidation biomarkers were measured. Results FABP4 was negatively associated with endothelial function, as measured by the IHR (r=-.226, P=.027) in T2D subjects. There was a significant inverse association of the IHR across FABP4 tertiles ( P=.023). In a stepwise multivariable linear regression model, FABP4 was a predictor of IHR in T2D patients ( P<.05). FABP4 levels were higher in T2D patients. We also observed a significant positive correlation between FABP4 and BMI (r=.211; P=.03) and Ab ox-LDL (r=.251; P=.01). The correlation between FABP4 and IHR was maintained after adjusting for these confounding variables. There were not significance differences in GIM and ABI among patients. Conclusion High circulating levels of FABP4 are associated with worse endothelial function, as measured by IHR in T2D patients. We suggest a direct effect of plasma FABP4 on the vascular endothelium in T2D patients.

Concentraciones plasmáticas de FABP4 y evolución del síndrome metabólico

Background Circulating FABP4 levels have been associated with metabolic alterations and have been considered a predictive biomarker of the development of metabolic syndrome (MS), independently of adiposity and insulin resistance in non-diabetic Asians. Objective To evaluate the relationship between changes in FABP4 levels and MS regression or progression in a group of subjects enrolled in a therapeutic lifestyle changes program. Patients and methods We included 140 subjects with abdominal obesity and increased overall cardiovascular risk, who were prospectively followed-up for 1 year. The association between changes in FABP4 levels and changes in MS and its components was evaluated. Changes in other biochemical parameters, anthropometric markers and vascular data were also investigated. Results We observed an increase in FABP4 levels associated with MS progression and a reduction in FABP4 levels associated with MS regression. The increase in FABP4 levels was associated with the development of both triglyceridemia and low levels of high-density lipoprotein (HDL)-cholesterol, while FABP4 reductions were associated with regression of abdominal obesity, low HDL-cholesterol and the basal glycemia criteria of MS. The predictors of MS progression were positive changes in insulin and waist circumference. The only independent predictor of MS regression was reduction in FABP4. Conclusions Variations in circulating FABP4 levels are associated with MS progression and regression. Given the impact of FABP4 on several MS components, a causal relationship between FABP4 reduction and MS regression cannot be excluded.

Fatty acid-binding protein 4 is associated with endothelial dysfunction in patients with type 2 diabetes

Objective Adipocyte fatty acid-binding protein (FABP4) plasma levels are higher in type 2 diabetes (T2D). Endothelial dysfunction is also common in T2D. We have investigated the relationship between circulating FABP4 levels and endothelial function in diabetic patients. Methods In 257 patients (105 diabetic and 152 non-diabetic) at increased risk of cardiovascular disease, we measured circulating FABP4, reactive hyperemia index (RHI) by peripheral artery tonometry, intima-media thickness, and biomarkers of inflammation, oxidation and endothelial function. Results In T2D subjects, FABP4 was negatively associated with endothelial function, as measured by RHI ( r = −0.226, P = 0.05). In a stepwise multivariate linear regression model, FABP4 was a predictor of RHI in T2D patients ( P = 0.04). Conclusion Circulating levels of FABP4 are inversely associated with endothelial function in T2D patients, as measured by RHI. We suggest a direct effect of plasma FABP4 on the vascular endothelium in those with T2D.

Fatty-acid binding protein 4 gene variants and childhood obesity: potential implications for insulin sensitivity and CRP levels

IntroductionObesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. FABP4 is a member of the intracellular lipid-binding protein family that is predominantly expressed in adipose tissue, and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to measure FABP4 plasma levels, assess FABP4 allelic variants, and explore potential associations with fasting glucose and insulin levels in young school-age children with and without obesity.MethodsA total of 309 consecutive children ages 5-7 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score >1.65) and non-obese (NOB). Fasting plasma glucose, lipids, insulin, hsCRP, and FABP4 levels were measured. HOMA was used as correlate of insulin sensitivity. Four SNPs of the human FABP4 gene (rs1051231, rs2303519, rs16909233 and rs1054135), corresponding to several critical regions of the encoding FABP4 gene sequence were genotyped.ResultsCompared to NOB, circulating FABP4 levels were increased in OB, as were LDL, hsCRP and HOMA. FABP4 levels correlated with BMI, and also contributed to the variance of HOMA and hsCRP, but not serum lipids. The frequency of rs1054135 allelic variant was increased in OB, and was associated with increased FABP4 levels, while the presence of rs16909233 variant allele, although similar in OB and NOB, was associated with increased HOMA values.ConclusionsChildhood obesity is associated with higher FABP4 levels that may promote cardiometabolic risk. The presence of selective SNPs in the FABP4 gene may account for increased risk for insulin resistance or systemic inflammation in the context of obesity.