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Proteomics and Protein Markers |
1 Department of Medicine;2
the Research Center of Heart, Brain, Hormone, and Healthy Aging;3
Department of Biochemistry; and4
Genome Research Center, University of Hong Kong, Hong Kong, China.
5 Department of Laboratory Medicine, Sternberk Hospital, Sternberk, The Czech Republic.
6 Clinical Biochemistry Unit, Queen Mary Hospital, Hong Kong, China.
aAddress correspondence to this author at: Department of Medicine, University of Hong Kong, L8-43, 21 Sassoon Road, Hong Kong, China. Fax 852-28162095; e-mail amxu{at}hkucc.hku.hk.
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Abstract |
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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) µg/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.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, interleukin-6, plasminogen activator inhibitor 1, and free fatty acids, contributes to the development of metabolic syndrome (6)(7).
Adipocyte-specific fatty acid–binding protein (A-FABP)
1
belongs to the fatty acid-binding protein superfamily whose members have relative molecular masses (Mr) of 
15 000, and it is highly expressed in adipose tissue (8)(9). A-FABP is a predominant cytosolic protein of mature adipocytes, accounting for 6% of total cellular proteins. This protein may be an important regulator of systemic insulin sensitivity and lipid and glucose metabolism (8). Mice deficient in A-FABP are protected from development of hyperinsulinemia, hyperglycemia, and insulin resistance in the context of both dietary and genetic obesity (10)(11). Adipocytes obtained from A-FABP–null mice had markedly reduced efficiency of lipolysis in vivo and in vitro (12)(13) and exhibited a 2- to 3-fold decrease in fatty acid release, suggesting that A-FABP mediates efflux of fatty acids in normal physiology (14). Furthermore, the acute insulin secretory response to ß-adrenergic stimulation was profoundly suppressed in A-FABP (–/–) mice compared with their wild-type littermates (13), suggesting that this protein might modulate systemic insulin sensitivity through its actions on other distal target tissues.
A-FABP is present in macrophages (9)(15), which have striking similarities to adipocytes in biology and function (16). The expression of A-FABP in macrophages can be induced by oxidized LDL (17) and by toll-like receptor agonists (18) and can be suppressed by the cholesterol-lowering statin drugs (19). In these cells, A-FABP modulates inflammatory cytokine production and cholesterol ester accumulation (20). In apolipoprotein (apo) E-deficient mice, ablation of the A-FABP gene conferred remarkable protection against atherosclerosis, which commonly occurs in this mouse strain (21)(22). Taken together, these animal studies demonstrate that A-FABP, by integrating metabolic and inflammatory pathways, provides a key link between various components of metabolic syndrome. Nevertheless, the clinical relevance of these findings remains to be confirmed.
The original purpose of our study was to use a proteomics approach based on 2-dimensional gel electrophoresis (2-DE) to systematically characterize adipokines secreted from adipocytes. Unexpectedly, we found that A-FABP, traditionally thought to be a cytoplasmic protein, was released from adipocytes into the bloodstream. We therefore designed the present study to investigate whether the circulating concentrations of A-FABP correlate with adiposity and components of the metabolic syndrome in humans.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To harvest proteins secreted by adipocytes, we washed cells 3 times with phosphate-buffered saline and then incubated them with serum-free medium for another 4 h. The medium was collected, filtered through a 0.20 µm filter, and then concentrated and desalted by use of a concentrator with a molecular mass cutoff of 5000 (Vivascience AG). We quantified the proteins with bicinchoninic acid (BCA) reagent, then separated 50 µg of the proteins by 2-DE and visualized them with silver staining, as we described previously (24)(25).
coupling of CNBR-activated sepharose beads with anti-human a-fabp4 antibody
Affinity-purified antihuman A-FABP (Biovendor Laboratory Medicine, Inc.) was coupled to Sepharose beads according to the manufacturer’s instructions (GE Healthcare). Briefly, 250 µg of the antibody solution (1 g/L) in 0.1 mol/L NaHCO3 was mixed with 500 µL of CNBr-activated Sepharose beads overnight at 4 °C with gentle shaking. After being washed and blocked with 0.1 mol/L Tris-HCl (pH 8.0), the beads were stored in 200 mL/L ethanol at 4 °C.
purification of a-fabp from human serum by affinity chromatography
Albumin and IgG, the 2 major components of human serum, were depleted by the ProteoExtract Albumin/IgG Removal Kit (Calbiochem), and the remaining supernatant was incubated with 100 µL of Sepharose beads coupled with rabbit nonimmune IgG to prevent nonspecific binding. The clarified supernatant was then incubated with 100 µL of Sepharose beads coupled with anti-human A-FABP IgG at 4 °C overnight. The beads were washed with Tris-buffered saline, and the bound protein complexes were eluted with 0.1 mol/L glycine-HCl (pH 2.5). The eluted fractions were concentrated, separated by 15% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), and visualized by silver staining.
protein identification by edman degradation sequencing and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry
Proteins of interest separated by 1- or 2-DE were excised and digested in gel with trypsin; the tryptic peptide mixtures were then fractionated by reversed-phase HPLC on a Jupiter 5 µC18 column (250 x 2.00 mm; Phenomenex Inc.) as we described previously (25). Well-separated fractions were collected and subjected to amino acid sequencing by Edman degradation using a PerkinElmer Life Sciences Procise Model 492 protein sequencer (24).
For matrix-assisted laser desorption/ionization time-of-flight mass spectrometric analysis, 0.5 µL of the tryptic peptide mixture or peptides separated by reversed-phase HPLC was mixed with an equal amount of -cyano-4-hydroxycinnamic acid matrix (10 g/L in 600 mL/L acetonitrile–3 mL/L trifluoroacetic acid), spotted on the sample plates, and air-dried. Reflectron MS analyses were performed on a Voyager DE PRO Biospectrometry Workstation (Applied Biosystems) equipped with a pulsed laser beam (nitrogen laser, 
= 337 nm). All ion spectra were recorded in the positive mode with an acceleration voltage of 20.0 kV. The spectrometer was externally calibrated by use of Cal Mix 2 standard mixture. Tandem MS (MS/MS) experiments were performed with a QSTAR XL quadrupole orthogonal acceleration time-of-flight mass spectrometer equipped with an oMALDI ion source (Applied Biosystems), as described previously (25).
human participants
We recruited a total of 229 persons from our previous cross-sectional Hong Kong Cardiovascular Risk Factor Prevalence Study (26)(27). The participants were stratified to lean [body mass index (BMI) <25 kg/m2] and overweight/obese (BMI 
25 kg/m2) groups. For some analyses, the overweight/obese participants were further classified into 2 BMI groups according to the guidelines of the World Health Organization: overweight (BMI = 25–29.9 kg/m2) and obese (BMI 30 kg/m2). The study protocol was approved by the Ethics Committee of the Medical Faculty, University of Hong Kong.
anthropometric and biochemical measurements
Anthropometric measurements (height, weight, waist circumference, BMI, and systolic and diastolic blood pressures) were performed as reported previously (26). The methods for measurement of biochemical variables, including fasting insulin and glucose concentrations, 2-h postprandial glucose concentrations, fasting lipid profiles (total cholesterol, LDL-cholesterol, HDL-cholesterol, and total serum triglycerides and free fatty acids) were described elsewhere (27)(28). The homeostasis model assessment (HOMA) of insulin resistance, a simple assessment of insulin sensitivity, was calculated with the following formula: fasting plasma glucose (mmol/L) x fasting insulin (mIU/L)/22.5. Body composition was determined by bioelectric impedance analysis (Model TBF-410; Tanita). The serum concentrations of adiponectin were quantified by an in-house ELISA, as we described recently (29).
The metabolic syndrome was defined, according to criteria proposed by the National Cholesterol Education Program’s Adult Treatment Panel III report (30), as the presence of 3 or more of the following abnormalities: (a) hypertension (systolic blood pressure 130 mmHg, diastolic blood pressure 85 mmHg, and/or receiving blood pressure–lowering drugs); (b) hyperglycemia [fasting serum glucose concentration 6.1 mol/L (110 mg/dL) and/or receiving glucose-lowering drugs]; (c) hypertriglyceridemia [fasting serum triglyceride concentration 1.69 mmol/L (150 mg/L)]; (d) low HDL-cholesterol [fasting serum HDL-cholesterol concentration <1.04 mmol/L (40 mg/dL) in males and <1.29 mmol/L (50 mg/dL) in females]; (e) central obesity (waist circumference 80 cm in females and 90 cm in males, according to the classification criteria for Asians) (31).
elisa for quantitative measurement of human a-fabp
The human A-FABP ELISA reagent sets were obtained from Biovendor Laboratory Medicine, Inc. Serum samples were diluted 1:10 before assay, then 100-µL volumes of diluted sera, calibrators, and quality-control samples were applied to 96-well microtiter plates coated with an affinity-purified goat anti-human FABP antibody. The assay was conducted according to the manufacturer’s instructions. A calibration curve was constructed by plotting the absorbance values at 450 nm vs the A-FABP concentrations of the calibrators, and concentrations of unknown samples were determined by use of this calibration curve. The intra- and interassay variations were evaluated by measuring 3 different samples in 10 replicates in a single assay, or in duplicate in 5 consecutive assays, respectively.
data analysis
All statistical calculations were performed with the SPSS 11.5 statistical software package (SPSS Inc.). We used the Pearson correlation coefficient to establish the association between A-FABP concentrations and various anthropometric and biochemical measures. Comparison of values between lean and overweight/obese individuals was made by one-way ANOVA. Participants were also stratified into 5 groups according to the number of components of the metabolic syndrome (0, 1, 2, 3, or 4). We used one-way ANOVA with a Scheffé-type multiple comparison test to compare serum A-FABP concentrations among these groups. All data are expressed as the mean (SD), and P values <0.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). MS-based peptide fingerprinting identified many of these proteins as previously described adipokines with typical secretory signal peptides such as adiponectin, adipsin, complement factor 3, and others (data not shown). Notably, 1 protein spot, with an apparent Mr of 15 000 and pI of 4.8, was found to be murine A-FABP. Image analysis with PDQUEST software (Bio-Rad Laboratories) revealed that this protein accounted for >1% of the total protein secreted from adipocytes. We further confirmed the identity of the protein by Edman degradation sequencing of 2 tryptic peptides derived from the protein spot. This analysis yielded the internal sequences EVGVGFAT and LGVEFDEITA, which exclusively matched amino acid residues 22–29 and 67–76 of murine A-FABP, respectively.
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Western blot analysis revealed that A-FABP was abundantly present inside the cells as well as in the extracellular medium (Fig. 1B
). On the other hand, ß-tubulin, a cytoskeleton protein, was detected only in the cell lysates but not in the extracellular culture medium of adipocytes, suggesting that A-FABP detected in the extracellular medium was not caused by nonspecific cell lysis.
a-fabp is present in human serum and is increased in overweight/obese individuals
To investigate whether A-FABP is a circulating protein, we subjected human serum to chromatographic purification using the anti-human A-FABP antibody (Biovendor Laboratory Medicine) as an affinity ligand. SDS-PAGE revealed a protein with an Mr 15 000 that was selectively eluted from the gel matrix coupled with the anti-A-FABP antibody (Fig. 2
). MS/MS analysis unequivocally identified the protein as A-FABP, indicating the presence of this protein in human serum. Notably, there were no noise signals for other types of FABPs, suggesting that the anti-A-FABP used in this study was highly specific to this protein.
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We next measured the serum concentrations of A-FABP in 100 lean and 129 overweight or obese individuals. The clinical and biochemical characteristics of these individuals are given in Table 1
. With a sandwich ELISA method recently developed by Biovendor Laboratory Medicine, Inc., we found that the assay is highly specific for human A-FABP, with no detectable cross-reactivity with other types of FABPs [heart-type FABP (H-FABP), liver-type FABP (L-FABP), or keratinocyte FABP (E-FABP)], leptin, adiponectin, resistin, tumor necrosis factor-, C-reactive protein, or interleukin-6. The intra- and interassay CVs were 3.7%–6.4% and 2.6%–5.3%, respectively. In lean individuals, mean (SD) serum concentrations of A-FABP were 20.0 (9.8) µg/L (range, 7.2–36.4 µg/L). In both men and women, the circulating concentrations of this protein in obese/overweight individuals were significantly higher than those in lean individuals (Table 2
). Notably, serum A-FABP concentrations in men were significantly lower than in women among obese/overweight individuals (P <0.01) but not in lean individuals. We observed a strong positive correlation between serum A-FABP concentrations and BMI in both men (r = 0.477; P <0.001) and women (r = 0.651; P <0.001; Fig. 3
).
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serum a-fabp concentrations are closely related to the components of metabolic syndrome
Several recent studies on animal models have demonstrated that A-FABP plays a central role in linking obesity with metabolic syndrome. We next investigated the relationship between serum A-FABP concentrations and various biochemical and anthropometric markers for metabolic syndrome in humans. Because there was a wide variation in BMI among the 36 obese individuals (ranging from 30.1 to 50.8 kg/m2) and a strong correlation between A-FABP and BMI, we excluded these obese individuals to ensure that the correlation analysis would be examined in a more homogeneous cohort. After adjustment for sex and age, serum concentrations of A-FABP were positively correlated with waist-to-hip ratio; waist circumference; fat percentage; systolic and diastolic blood pressure; fasting serum concentrations of insulin, triglycerides, and LDL-cholesterol; 2-h postprandial glucose; and the HOMA index (Table 3
). On the other hand, A-FABP was negatively correlated with fasting serum concentrations of HDL-cholesterol. Notably, the correlations of serum A-FABP with fat percentage and triglyceride, insulin, and 2-h postprandial glucose concentrations were significant even after adjustment for BMI.
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Age- and sex-adjusted serum concentrations of A-FABP were inversely associated with circulating concentrations of adiponectin, an important adipokine with antidiabetic and antiatherogenic activities (32). After adjustment for serum adiponectin, the association of serum A-FABP concentrations with triglycerides (r2 = 0.319; P <0.001), LDL (r2 = 0.148; P <0.05), HDL (r2 = –0.213; P <0.001), fasting insulin (r2 = 0.315; P <0.001), and 2-h postpranidal glucose (r2 = 0.212; P <0.05) remained significant, whereas its relationship with systolic blood pressure (r2 = 0.002; P = 0.984) and diastolic blood pressure (r2 = 0.084; P = 0.415) did not persist. This result suggests that the association of A-FABP with blood pressure is largely attributable to its inverse correlation with serum adiponectin.
On the basis of National Cholesterol Education Program criteria, metabolic syndrome was diagnosed in 32.7% of the 229 individuals studied. By stratification of serum concentrations of A-FABP, we found that the prevalence of metabolic syndrome in individuals with A-FABP >35 µg/L was 54.5% in women and 71.4% in men. On the other hand, the prevalence rate of this disorder in individuals with A-FABP <15 µg/L was only 2% in women and 6.9% in men. To further explore the relationship between A-FABP and metabolic syndrome, we stratified the mean concentrations of serum A-FABP by the number of components of the metabolic syndrome present in each individual (Fig. 4
). Mean A-FABP concentrations for those with 0, 1, 2, 3, or 4 components of metabolic syndrome were 16.63, 17.82, 20.98, 29.34, and 37.67 µg/L in men and 17.81, 20.1, 26.35, 37, 42, and 43.21 µg/L in women, respectively. The serum concentrations of A-FABP increased significantly as the number of components of metabolic syndrome increased. In both sexes, a linear and significant trend was observed (P <0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our immunoassay results for human A-FABP revealed that in lean persons the circulating concentration of this protein is substantially higher than those of several other major adipokines and/or cytokines secreted from adipose tissue, including resistin, leptin, tumor necrosis factor-, interleukin-6, and C-reactive protein (27)(37)(38). In overweight/obese persons, we found that circulating A-FABP was markedly increased in both men and women. The strong positive association between serum A-FABP concentrations and indicators of adiposity (BMI, waist-to-hip ratio, waist circumference, and fat percentage) further suggests that adipose tissue, which is composed of adipocytes and macrophages, is probably the major contributor of A-FABP secreted into the circulation. For serum A-FABP in obese individuals, we observed a sexual dimorphism similar to those that occur with many adipokines derived from adipose tissue (29)(39). This sex difference may be the result primarily of the relatively higher fat percentage in women than in men. Indeed, we found that the fat percentage is a determinant of circulating A-FABP concentrations. In addition, the sex difference in regional fat distribution might also contribute to the sexual dimorphism of A-FABP in overweight/obese men and women. Women generally have more subcutaneous fat than men, whereas men have more abdominal (visceral) fat (40), and different fat depots have differential gene expression. For example, it has previously been shown that visceral fat produces more angiotensinogen, interleukin-6, and plasminogen activator inhibitor-1, but less leptin and adiponectin than subcutaneous fat (41). Further study is needed to investigate whether fat depots differ in the production of A-FABP in humans.
Several previous studies in A-FABP–null mice have suggested that A-FABP plays a key role in the link between obesity and various features of metabolic syndrome (8)(21). Earlier reports showed that mice with targeted disruption of the A-FABP gene alone exhibited moderate improvement in systemic glucose and lipid metabolism and alleviation of insulin resistance associated with both dietary (11) and genetic (10) obesity. Nevertheless, study results suggest that dramatic compensatory up-regulation of E-FABP (also called mal1), an otherwise minor form of adipocyte FABP, in adipose tissue of A-FABP–null mice might lead to underestimation of phenotypic changes (42). To overcome this limitation, mice with targeted disruption of both A-FABP and E-FABP were developed (43). Mice lacking these 2 FABPs exhibited a striking phenotype with almost complete protection against diet-induced obesity, insulin resistance, dyslipidemia, type 2 diabetes, and fatty liver disease. In addition, compared with controls in the apo E–/– model, mice with either A-FABP deficiency alone (21) or combined deficiency of both A-FABP and E-FABP (22) showed as much as a 90% lower rate of arteriosclerosis throughout the aorta. Remarkably, when mice were challenged with a high-fat atherogenic Western diet for 1 year, the survival rates of apo E–/– mice null for both FABPs were 67% higher than those of apo E–/– controls (22). In addition, adenovirus-mediated overexpression of A-FABP facilitated foam cell formation in human macrophages (44).
Consistent with these animal findings, our study results in humans demonstrated a close positive association between circulating concentrations of A-FABP and features of the metabolic syndrome, including adverse lipid profiles (increased serum triglycerides and LDL-cholesterol and decreased HDL-cholesterol), fasting insulin, 2-h postprandial glucose, HOMA index, and systolic and diastolic blood pressure. Notably, the correlation between circulating concentrations of A-FABP and serum concentrations of triglycerides, 2-h postprandial glucose, and fasting insulin remained significant even after adjustment for BMI, suggesting that A-FABP might be an independent contributor to hypertriglyceridemia and glucose intolerance in humans. Our clinical data, taken together with the findings from A-FABP–null mice, support the notion that A-FABP might be a central player in the development of key pathologies associated with metabolic syndrome in humans.
The physiologic functions of circulating A-FABP remain to be determined. Like most FABPs, A-FABP can bind with a variety of hydrophobic lipid ligands known to influence systemic metabolism and inflammation (8)(45). Cytoplasmic A-FABP has been proposed to be involved in the intracellular trafficking and targeting of fatty acids inside cells (46). Nevertheless, this local action in adipocytes cannot fully account for the observed metabolic effect of A-FABP on its several distal targets, such as the liver and muscle (14)(43). Circulating A-FABP might participate in transporting free fatty acids or other types of lipid hormones, which in turn modulate systemic insulin sensitivity and energy metabolism, in the bloodstream. Indeed, a recent report has demonstrated that retinol-binding protein 4, another small lipid-binding protein produced in adipose tissue and liver, functions as an endocrine hormone that contributes to obesity-related insulin resistance and diabetes in mice (47). Research is ongoing in our laboratory to define the potential roles of circulating A-FABP in mediating the metabolic and inflammatory effects of this protein in mice.
In summary, our study demonstrates for the first time that A-FABP is a circulating biomarker of adiposity in humans. Our clinical data, taken together with the previous findings in animal models, support the central role of A-FABP in linking obesity with key components of the metabolic syndrome and suggest that this protein might represent a promising diagnostic marker for these disorders. Further prospective studies are needed to evaluate whether measurement of circulating concentrations of A-FABP can be used to predict the risk of diabetes and cardiovascular diseases.
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Acknowledgments |
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Footnotes |
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References |
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activation induces the expression of the adipocyte fatty acid binding protein gene in human monocytes. Biochem Biophys Res Commun 1999;261:456-458.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve] and I
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J. Bronsky, M. Karpisek, E. Bronska, M. Pechova, B. Jancikova, H. Kotolova, D. Stejskal, R. Prusa, and J. Nevoral Adiponectin, Adipocyte Fatty Acid Binding Protein, and Epidermal Fatty Acid Binding Protein: Proteins Newly Identified in Human Breast Milk Clin. Chem., September 1, 2006; 52(9): 1763 - 1770. [Abstract] [Full Text] [PDF]
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; n = 121) and women (
; n = 108).