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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.
Metabolic syndrome refers to a cluster of cardiovascular risk factors, including central obesity, insulin resistance, dyslipidemia, and hypertension.[45] A-FABP is a predictive circulating biomarker of components of metabolic syndrome.[17][18] Over the past 5 years, novel discoveries regarding the role of A-FABP in metabolic syndrome have been made (Table 1).
Year | Diseases/Conditions | Subjects/Animals/Methods | Main Novel Findings | Reference |
Metabolic syndrome | ||||
2016 |
Type-2 diabetes/Obesity |
48 non-obese subjects newly diagnosed with type 2 diabetes; 42 obese subjects newly diagnosed with type 2 diabetes; 30 simple obese subjects; and 30 matched normal subjects |
1. Serum A-FABP levels were significantly correlated with HbA1c 2. Serum A-FABP levels correlated with levels of inflammatory cytokines (C-reactive protein and IL-6) in obese diabetic subjects |
Niu G et al. [46] |
2017 |
Obesity |
22 obese middle-aged men randomized to exercise training group or control group |
Exercise training reduced A-FABP concentrations and improved glucose metabolism in obese middle-aged men |
Bahrami Abdehgah E et al. [47] |
2017 |
Lipotoxicity/ ER stress/Autophagy |
Macrophages isolated from A-FABP knockout mice treated with palmitic acid and/or infected with adenoviruses over-expressing A-FABP |
1. Prolonged treatment of palmitic acid enhanced the expression of A-FABP associating with increased endoplasmic reticulum stress and reduced autophagic flux in macrophages 2. A-FABP suppressed PA-induced JAK-dependent autophagy thus promoted ER stress and inflammation in macrophages. |
Hoo RL et al. [48] |
2017 |
Adaptive thermogenesis |
A-FABP knockout mice were infused with recombinant A-FABP after HFD for 4 weeks |
1. A-FABP levels were increased in both white and brown adipose tissue in response to thermogenic stimuli 2. A-FABP deficiency impaired adaptive thermogenesis in mice, which were reversed by replenishment of recombinant A-FABP 3. A-FABP induced the expression of type-II iodothyronine deiodinase in brown adipose tissue, promoting the conversion of thyroid hormones from its inactive form T4 to active form T3, thus enhancing thermogenic activity. |
Shu L et al. [49] |
2018 |
Glucose fluctuation on macrophage inflammation |
Human monocytic THP-1 cells were exposed to normal, constant high, or intermittent high glucose |
1. Intermittent high glucose induced A-FABP expression and release of pro-inflammatory cytokines. Treatment with constant high glucose showed similar effects but with less evident changes. 2. Inhibition of JNK signalling pathway inhibited glucose-induced A-FABP expression and production of pro-inflammatory cytokines |
Li H et al. [50] |
2020 |
Lipolysis/ Pro-inflammation |
Adipocytes were co-treated with recombinant A-FABP and A-FABP inhibitor (SB203580/I-9) or vehicle; Male mice were subcutaneous injected with recombinant A-FABP |
1. Exogenous treatment of A-FABP resulted in anti-adipogenesis by inducing lipolysis (via p38/HSL signalling) and inflammation (via NF-κB signalling) 2. The pro-inflammatory and pro-lipolytic effects of exogenous A-FABP were reversed by A-FABP inhibitor |
Dou HX et al. [51] |
CVD | ||||
2016 |
Cardiovascular mortality |
950 male subjects with type 2 diabetes with an average follow-up for 22 years |
Higher levels of A-FABP were significantly associated with higher CVD mortality |
Liu G et al. [52] |
2016 |
Coronary atherosclerosis |
Human macrophages and coronary artery-derived smooth muscle cells and endothelial cells were treated with exogenous A-FABP |
1. Exogenous treatment with A-FABP stimulated the inflammatory response in vascular endothelial cells in a dose-dependent manner 2. Serum A-FABP levels were correlated with coronary sinus A-FABP 3. A-FABP in coronary sinus and aortic root independently predicted severity of coronary stenosis |
Furuhashi M et al. [53] |
2016 |
Macrophage inflammation |
Macrophages from A-FABP knockout or wild-type mice |
1. Sirtuin 3 was upregulated in A-FABP deficient macrophages 2. Elevated sirtuin 3 attenuated lipopolysaccharide-induced expression of inflammatory cytokines, inducible nitric oxide synthase, and cyclo-oxygenase 2 |
Xu H et al. [54] |
2016 |
Heart failure |
Cardiomyocyte-specific A-FABP transgenic mice treated with A-FABP inhibitor (BMS309403) |
1. Over-expression of A-FABP in cardiomyocytes activated ERK signaling pathway and upregulated the expression of cardiac hypertrophic marker genes 2. Aggravation of cardiac hypertrophy was alleviated with A-FABP inhibitor |
Zhang J et al. [55] |
2017 |
Vascular Injury/ Neointima formation |
1. A-FABP deficient mice and relative wild-type mice subjected to wire-induced vascular injury 2. Human coronary artery endothelial cells (HCAECs) and human coronary smooth muscle cells were infected with adenovirus-overexpressing A-FABP or treated with anti-A-FABP antibody. |
1. A-FABP deficient mice exhibited decreased neointima formation in response to wire-induced vascular injury. 2. Human coronary artery endothelial cells secreted A-FABP 3. Adenovirus-mediated overexpression of A-FABP in human coronary artery endothelial cells increased inflammatory cytokines and reduced phosphorylation of nitric oxide synthase 3 4. Ectopic A-FABP increased proliferation and migration of human coronary smooth muscle cells and vascular endothelial dysfunction, which were attenuated by treatment with anti-A-FABP antibody |
Fuseya T et al. [56] |
2018 |
Carotid atherosclerosis |
281 subjects without medication followed-up for 3 years |
1. Serum A-FABP levels were significantly correlated with CIMT 2. Yearly changes in CIMT were positively associated with baseline levels of A-FABP |
Furuhashi M et al. [57] |
2017 |
Acute ischemic stroke |
737 patients with acute ischemic stroke |
1. A-FABP levels were associated with poor functional outcome and mortality 2. Addition of A-FABP improved the prognostic accuracy of National Institutes of Health Stroke Scale score |
Tu WJ et al. [58] |
2020 |
Ischemic stroke |
30 patients with acute ischemic stroke; A-FABP knockout or wild-type mice subjected to middle cerebral artery occlusion; |
1. A-FABP levels were correlated with cerebral infarct volume and levels of matrix metalloproteinases-9 in patients with ischemic stroke 2. Ischemia-induced elevation of A-FABP in macrophages and microglial cells contributed to degradation of tight junction proteins and blood-brain barrier leakage by inducing metalloproteinases-9 expression |
Liao B et al. [23] |
2020 |
Heart failure; atherosclerotic cardiovascular diseases |
176 patients with type 2 diabetes without established CVD followed-up for 28 months |
1. A-FABP levels at baseline was associated with the development of left ventricular hypertrophy and diastolic dysfunction 2. A-FABP levels at baseline predicted the development of major adverse cardiovascular events (composite of cardiovascular death, hospitalization for heart failure, non-fatal myocardial infarction, and stroke) |
Wu MZ et al. [59] |
2020 |
Metabolic syndrome; coronary artery disease |
37 metabolic syndrome patients undergoing coronary artery bypass grafting (CABG) for underlying coronary artery disease and 23 patients without CAD undergoing heart valve surgery (control group) |
1. A-FABP mRNA expression in epicardial adipose tissue was significantly elevated in patients with metabolic syndrome and coronary artery disease 2. The extent of coronary atherosclerosis was significantly associated with the level of expression of A-FABP mRNA in epicardial adipose tissue |
Gormez et al. [60] |
2021 |
Heart failure |
50 patients with heart failure with preserved ejection fraction and 150 patients with elevated cardiometabolic risk |
1. A-FABP levels were associated with important hemodynamic indices, including higher central systolic and diastolic blood pressures 2. Compared to central hemodynamic information alone, the addition of A-FABP levels improved HF risk classification |
Yen et al. [61] |
Insulin resistance refers to the impaired response of targeted cells to insulin action. Among the risk factors, obesity is the most critical one, as the aberrant release of adipose tissue-derived NEFA, glycerol, adipokines, and proinflammatory cytokines contribute to insulin resistance and eventually causes pancreatic β-cell dysfunction.[78]
Clinical studies identified strong positive correlations between A-FABP, insulin resistance, and type 2 diabetes,[17][18][22][65][66][67][79][80][81][82] suggesting A-FABP as a biomarker of insulin resistance. Carriers of genetic variant (rs77878271) of T-87C polymorphism in the functional promoter of A-FABP gene with reduced A-FABP expression had a lower risk of developing type 2 diabetes.[83] A study investigating the effects of exercise training on insulin resistance in middle age obese men also showed that improvement in glucose metabolism was significantly correlated with reduction in circulating A-FABP.[47]
Animal studies also supported that A-FABP acts as a mediator of insulin resistance. In the context of DIO, A-FABP-deficient mice showed improvement in insulin sensitivity and glucose-stimulated insulin secretion.[70][84][85] The protection against the development of insulin resistance by A-FABP deficiency could be attributed to several mechanisms. A-FABP deficiency generates a lipid environment that is highly favorable for insulin action: mice lacking A-FABP had altered lipid composition in muscular tissue (upregulation of shorter chain [12:0 and 14:0] fatty acids, and downregulation of longer chain [16:0 and 18:0] fatty acids), leading to an upregulation in insulin-stimulated phosphorylation of Akt and protecting against high-fat-induced insulin resistance, thus enhancing the insulin signaling cascade.[84] The basal level and leptin-stimulated activity of AMP-K-α1, an important energy sensor in muscular tissue, were also elevated in A-FABP-deficient mice when compared to wild-type mice.[84] Furthermore, A-FABP-deficient DIO mice not only exhibited attenuation in beta-adrenergic-stimulated lipolysis[74][85] but also shown reduced secretion of inflammatory cytokines, such as TNFα,[70] when compared to their relative controls. The treatment of human THP-1 macrophages with intermittent high glucose stimulated the expression of A-FABP, which subsequently mediated inflammatory cytokine (TNF-α and IL-1β) secretion through activating TLR4/p-JNK signaling cascade,[50] which implicates the additional regulatory effect of A-FABP on inflammation in response to glucose fluctuation under insulin resistance.
Dyslipidemia includes increased low-density lipoproteins (LDLs), decreased high-density lipoproteins (HDLs), and increased fasting and postprandial triglyceride (TG)-rich lipoproteins (very-low-density lipoproteins [VLDL] and chylomicrons).[86][87] The mechanism through which dyslipidemia develops is closely related to insulin resistance,[88] as unrestrained lipolysis leads to an increased hepatic flux of FFA, contributing to increased hepatic TG, hence VLDL production.[89][90] Lipid overload in non-adipose tissues causes cellular dysfunction and apoptotic cell death, leading to lipotoxicity.[91] Clinical studies have shown a positive correlation of A-FABP with hypertriglyceridemia and LDL, as well as an inverse correlation with HDL.[17][18][65][66][67][79][81][83]
Aside from the effects of A-FABP on lipolysis, it also potentiates dyslipidemia-related lipotoxicity and chronic inflammation. In macrophages, A-FABP promotes toxic lipid-induced ER stress, leading to the exaggeration of inflammation via suppressing Janus kinase (JAK) 2-dependent autophagy.[48] Palmitic acid-mediated elevation of A-FABP in macrophages downregulated the autophagy-related protein 7, leading to the suppression of autophagy and increase of ER stress.[48] On the contrary, in A-FABP deficient macrophages, the phagocytic activity was significantly higher, the LPS-INFγ-induced M1 macrophage polarization was attenuated, while the IL4-induced M2 markers were markedly enhanced.[48] These findings implicate that A-FABP is a critical player in lipotoxicity-related inflammatory disorders.
Cardiovascular disease (CVD), including myocardial infarction (MI), stroke, and peripheral vascular disease, are the leading causes of death worldwide.[102] Atherosclerosis is the predominant cause of these medical conditions.[103] In multiple long-term follow-up studies of various patient cohorts, circulating levels of A-FABP were shown to predict the development of CVD and cardiovascular mortality.[52][79][104][105] The important findings on the role of A-FABP in CVD in recent years are summarized in Table 1.
Atherosclerosis is characterized by the narrowing/hardening of arteries caused by the buildup of plaque, which is made up of substances, including fats and cholesterol.[103] Risk factors, such as endothelial dysfunction, dyslipidemia, hypertension, and type 2 diabetes, contribute to the pathogenesis of atherosclerosis.[106][107] The mechanisms through which atherosclerosis develops are manifold. Mechanistically, endothelial dysfunction-associated reduction of nitric oxide (NO) production, generation of reactive oxidative species (ROS), and increase in oxLDL trigger an inflammatory response, thus leading to atherosclerosis.[15] Apart from metabolic risk factors, smoking is also another major contributory factor for the development of atherosclerosis through multiple mechanisms, including promoting the formation of ROS, causing endothelial dysfunction, and inducing a systemic inflammatory state.[108] Indeed, A-FABP has been implicated in the development of endothelial dysfunction through mediating production of nitric oxide as well as systemic inflammation.[100] Although no prior studies have comprehensively evaluated the association between A-FABP and cigarette smoking, A-FABP levels were found to be higher among women exposed to polycyclic aromatic hydrocarbons, a major constituent in cigarettes that triggers an inflammatory reaction.[109]
Human studies have shown a strong association between A-FABP and atherosclerotic conditions (Table 2). Circulating levels of A-FABP are closely associated with carotid intima-media thickness (CIMT), a well-established marker of atherosclerosis.[57][110][111] In Chinese cohorts, serum A-FABP levels were independently associated with CIMT in women but not in men,[110][111] which might be due to lower levels of A-FABP in men. Higher basal levels of A-FABP were also associated with larger changes in CIMT, suggesting that A-FABP predicts the progression of atherosclerosis.[57] Moreover, expression of A-FABP was elevated in carotid plaques in patients with CVD and was associated with plaque vulnerability.[112][113] Patients with higher baseline levels of A-FABP had an increased risk of subclinical atherosclerosis in a cohort of Chinese patients.[114] A recent study also showed a significant association between A-FABP expression levels in epicardial adipose tissue and the extent of coronary atherosclerosis in patients with metabolic syndrome and coronary artery disease (CAD).[60] On the contrary, patients with T-83C polymorphism exhibited lower A-FABP expression in carotid plaques and adipose tissue, had a lower prevalence of carotid plaques, reduced CIMT, and a reduced risk of developing CAD and MI.[83][113] By using coronary thrombectomy specimens from patients with acute myocardial and autopsy coronary artery and specimens from patients with ischemic heart disease, the elevated expression of A-FABP was identified in macrophages within atherosclerotic lesions and epicardial/perivascular adipocytes.[53]
Published Year |
Cohort |
Country |
Follow-Up Years |
Main Findings |
Conclusion |
Reference |
2007 |
479 subjects |
China |
/ |
1. Serum A-FABP levels were higher in women than in men 2. Serum A-FABP levels were positively correlated with CIMT in both sexes, but an independent association was only observed in women 3. Serum A-FABP levels were independently associated with age and hypertension in women |
A-FABP levels are independently associated with carotid atherosclerosis in women |
Yeung DC et al. [110] |
2010 |
125 subjects with CAD and 120 control subjects |
Japan |
/ |
1. CAD patients had higher A-FABP levels compared to controls 2. Serum A-FABP levels were independently associated with plaque volume in CAD patients 3. Serum A-FABP levels were positively correlated with BMI, IL-6, and hsCRP, and were negatively correlated with HDL-cholesterol and serum adiponectin in CAD patients |
Increased serum A-FABP is significantly associated with a greater coronary plaque burden |
Miyoshi T et al. [20] |
2013 |
1847 subjects without previous CVD |
China |
12 years |
1. Higher baseline levels of A-FABP were associated with development of CVD 2. Addition of A-FABP to the traditional risk factor model improved the predictive performance |
Circulating A-FABP level independently predicts the development of CVD |
Chow WS et al. [79] |
2013 |
104 overweight/obese women (BMI ≥ 25 kg/m2) and 76 age-matched healthy controls (BMI < 25 kg/m2) |
Poland |
/ |
1. A-FABP concentration was correlated with insulin resistance 2. A-FABP was an independent predictor of triglyceride and HDL-cholesterol 3. A-FABP discriminated overweight/obese patients from healthy individuals |
A-FABP is a predictor of atherogenic risk profile |
Mankowska-Cyl A et al. [82] |
2014 |
2253 CVD-free subjects with normal glucose tolerance |
China |
/ |
A-FABP levels correlated with CIMT in men and in women (both premenopausal and postmenopausal), but an independent association was only observed in women |
Serum A-FABP levels are independently associated with subclinical atherosclerosis in pre- and post-menopausal women with normal glucose tolerance |
Hao Y et al. [111] |
2018 |
170 subjects with newly diagnosed type 2 diabetes |
China |
8 years |
Patients with higher baseline levels of A-FABP had an increased risk of developing subclinical atherosclerosis at 8 years |
Circulating A-FABP levels independently predict the development of subclinical atherosclerosis in type 2 diabetes patients |
Xiao Y et al. [114] |
2018 |
281 subjects without medication |
Japan |
3 years |
1. Serum A-FABP levels were significantly correlated with CIMT 2. Yearly changes in CIMT were positively associated with baseline levels of A-FABP |
A-FABP concentration is an independent predictor of the progression of carotid atherosclerosis |
Furuhashi M et al. [57] |
2020 |
176 patients with type 2 diabetes without established CVD followed-up for 28 months |
China |
28 months |
1. A-FABP levels at baseline was associated with the development of left ventricular hypertrophy and diastolic dysfunction 2. A-FABP levels at baseline predicted the development of major adverse cardiovascular events (composite of cardiovascular death, hospitalization for heart failure, non-fatal myocardial infarction, and stroke) |
A-FABP is able to predict adverse cardiovascular outcomes in diabetic patients |
Wu MZ et al. [59] |
Animal studies showed that A-FABP mediates the pathogenesis of atherosclerosis via inducing endothelial dysfunction, [15][100] vascular smooth muscle cell invasion,[53][56][115] foam cell formation,[11][100] and inflammatory response.[13][115] On the contrary, A-FABP deficiency in apolipoprotein E (ApoE)–deficient mice protected against atherosclerosis[9][116][117] and even high-fat diet–induced advanced atherosclerosis[118].
In ApoE-/- mice, who developed atherosclerotic plaques spontaneously, the presence of A-FABP was observed in the aortic endothelium from 12 weeks, while pharmacological inhibition of A-FABP by BMS309403 significantly improved endothelial function through rescuing the eNOS-NO signaling pathway.[15] Consistent with in vivo studies, lipid-induced elevation of A-FABP in human microvascular endothelial cells was accompanied with reduced phosphorylated eNOS and NO production, which was reversed upon BMS309403 treatment.[15] A-FABP was also induced in endothelial cells of the hyperplastic neointima of mice subjected to wire-induced vascular injury.[56] In human coronary artery endothelial cells (HCAECs), A-FABP expression was induced upon vascular endothelial growth factor (VEGF) or hydrogen peroxide (H2O2) treatment.[56] Adenovirus-mediated A-FABP overexpression inhibited the VEGF or insulin-stimulated eNOS phosphorylation and induced pro-inflammatory cytokine/adhesion molecules expression.[56] In human vascular endothelial cells (HUVECs), exogenous treatment of recombinant A-FABP (rA-FABP) also reduced the level of phosphorylated eNOS.[53] Upon palmitic acid treatment, rA-FABP not only further reduced the p-eNOS, but also upregulated the expression of pro-inflammatory cytokines, including MCP-1, IL-6, and TNFα.[53] Moreover, r-A-FABP treatment impaired the insulin-mediated eNOS pathway in vascular endothelial cells by inhibiting insulin receptor substrate 1 (IRS1) and Akt activation,[100] which implicates the mechanistic linkage between circulating A-FABP and endothelial cell dysfunction in diabetes. Furthermore, rA-FABP stimulated cell proliferation and migration of human coronary artery smooth muscle cells (HCASMCs) through upregulating cell cycle regulations (cyclin D1, CCL2, and MMP2) via activating c-jun and c-myc in a MAPK-dependent manner.[116] It also induced pro-inflammatory cytokine expression in HCASMCs.[53][56][115]
A-FABP plays a critical role in foam cell formation and the subsequent development of cholesterol-rich lesions. In ApoE-/- mice with macrophage-specific A-FABP deficiency, the reduction in atherosclerotic lesions was comparable with ApoE-/- mice with global A-FABP deficiency, suggesting the independent role of macrophage A-FABP in the pathogenesis of atherosclerosis.[9] In macrophages, A-FABP is induced by LPS[9][13][14] through activating JNK-c-Jun signaling[13] and oxLDL via activating NF-κB and PKC signaling pathways and PPARγ.[11][117] A-FABP-deficient macrophages not only exhibited a reduced capacity for inflammatory cytokine production[9][14] but also showed reduced total cholesterol and cholesterol ester content, due to accelerated cholesterol efflux.[14] A-FABP regulates cholesterol trafficking through mediating the PPARγ-LXRα-ABCA1 pathway.[14]
In addition, A-FABP promotes atherosclerosis by mediating inflammatory responses in macrophages, T cells, and dendritic cells.[13][115] A-FABP-deficient mice exhibited a significantly reduced expression of inflammatory cytokines[119] and inflammasome activation.[54][120] In macrophages, A-FABP mediates the inflammatory response induced by various stimulators. In response to LPS, A-FABP forms a positive feedback loop with JNK/AP-1, thereby upregulating the expression of inflammatory cytokines in macrophages.[13] On the other hand, in response to LPS or CD154 stimulation, A-FABP activates the IκB/NF-κB pathway, thus inducing the inflammatory activity of macrophages.[14] Upon the stimulation of palmitic acid, elevated A-FABP provoked the toxic lipid-induced ER stress via inhibiting the JAK2-dependent autophagy, which in turn triggered M1 macrophage polarization and the inflammatory cytokine expression.[48] In response to intermittent high glucose treatment, the activation of TLR4/p-JNK cascade upregulated both A-FABP expression and inflammatory cytokine secretion, which implicates that A-FABP might also be involved in the glucose fluctuation-associated inflammatory response.[50] A-FABP also activates the IκB/NF-κB pathway in T cells and dendritic cells, thus inducing inflammatory cytokine secretion.[115]