Adipocyte fatty-acid-binding protein

Adipocyte fatty-acid-binding protein, aP2 (FABP4, AFABP) is expressed in adipocytes and macrophages, and integrates metabolic and inflammatory responses. It is a member of the intracellular fatty-acid−binding protein (FABP) family. Cytoplasmic FABPs are small proteins that are expressed in a highly tissue-specific manner and bind to fatty acids. AFABP is primarily detected in adipose tissue and its expression is highly regulated during differentiation of adipocytes. Previous in vitro studies have established that hormone sensitive lipase (HSL) and adipocyte fatty acid-binding protein (AFABP) form a physical complex that presumably positions the FABP to accept a product fatty acid generated during catalysis.

Adipocyte fatty-acid-binding protein knock-out

Recent studies in AFABP-deficient mice have shown that loss of this protein has a critical impact on several aspects of the metabolic syndrome. First, lack of AFABP provides significant protection from hyperinsulinemia and insulin resistance associated with dietary or genetic obesity. Second, AFABP contributes to improved systemic glucose and lipid metabolism in the setting of dietary or genetic obesity and alters the rate of adipocyte lipolysis. As both insulin resistance and abnormal lipid metabolism are risk factors for cardiovascular disease, it is possible that AFABP influences the development of atherosclerosis by modulating these factors.

As in adipocytes, production of TNF-alpha is greatly reduced in AFABP-/- macrophages compared with wild-type controls. Other inflammatory cytokines such as IL-1 and IL-6 are also suppressed in AFABP-/- macrophages. Moreover, AFABP-/- macrophages display significantly decreased intracellular cholesterol ester accumulation in vitro and secrete highly reduced quantities of TNF-alpha, MCP-1 and IL-6 upon exposure to modified lipoprotein. These results indicate that AFABP has a significant role in two important aspects of macrophage biology that are highly relevant to the pathogenesis of atherosclerosis.

A second fatty acid-binding protein, mal1, also is expressed in adipocytes and macrophages, and mal1 deficiency produces similar effects on insulin resistance. The hypothesis was tested that combined aP2 and mal1 deficiency would produce synergistic effects on metabolism and reduce atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice (3KO mice). Lean 3KO mice had significantly lower serum cholesterol and triglycerides as well as improved insulin and glucose tolerance as compared with controls. Analysis of atherosclerotic lesions in the 3KO mice showed dramatic reductions in both early (20 weeks) and late-stage (60 weeks) atherosclerosis. Strikingly, survival in the 3KO mice was improved by 67% as compared with apoE-/- controls when challenged with the Western diet for 1 year

Adipocyte fatty-acid-binding protein inhibition

Orally active small-molecule inhibitor of AFABP is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. Targeting AFABP with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Adipocyte fatty-acid-binding protein regulation

The expression of AFABP mRNA is transcriptionally controlled by fatty acids. Expression of macrophage AFABP is induced on TLR activation and parallels increases in cholesteryl ester and triglyceride levels. These findings provide a molecular link between the known roles of TLR and AFABP in foam cell formation.

Adipocyte fatty-acid-binding protein in Airway Epithelia

AFABP, in addition to being abundantly expressed by adipocytes, is also expressed by human airway epithelial cells and shows a striking upregulation following stimulation of epithelial cells with the Th2 cytokines IL-4 and IL-13.

Adipocyte fatty-acid-binding protein in serum

A-FABP is released from adipocytes and is abundantly present in human serum. Mean (SD) circulating concentrations of A-FABP are significantly higher in overweight/obese than in lean persons [32.3 (14.8) vs 20.0 (9.8) microg/L; P < 0.001]. Age- and sex-adjusted serum A-FABP concentrations correlate positively (P < 0.005) with waist circumference, blood pressure, dyslipidemia, fasting insulin, and the homeostasis model assessment insulin resistance index. Moreover, a significant increase in A-FABP concentrations corresponding with increases in the number of components of the metabolic syndrome (P < 0.05) was observed.

In a longitudinal study, it was further evaluated the prospective association of A-FABP with the metabolic syndrome (MetS) as defined by the updated National Cholesterol Education Program criteria. 495 nondiabetics were prospectively followed up for 5 years. The relationship of serum A-FABP with the MetS and its components was investigated. At baseline, high A-FABP levels were associated with the MetS (odds ratio, 4.0; 95% CI, 1.5 to 10.4; highest versus lowest sex-specific tertile, adjusted for age, body mass index, the homeostasis model assessment index for insulin resistance, C-reactive protein, and adiponectin, P=0.005). On long-term follow-up, subjects with higher baseline A-FABP levels had progressively worse cardiometabolic risk profile and increasing risk of the MetS. Among 376 subjects without the MetS at baseline, 50 had developed it at 5 years. Apart from the homeostasis model assessment index for insulin resistance (P=0.001), baseline A-FABP was the only independent predictor of the development of the MetS during the 5-year follow-up (odds ratio, 4.7; 95% CI, 1.8 to 11.9; highest versus lowest sexspecific tertile, P=0.001, adjusted for the homeostasis model assessment index for insulin resistance and body mass index). A-FABP was predictive of the MetS even after adjustment for each of its individual components. Thus, circulating A-FABP predicts the development of the MetS independently of adiposity and insulin resistance.

Elevated plasma A-FABP concentrations in morbidly obese subjects are reduced after gastric banding-induced weight loss. This suggests that FABP may be associated with improvement of metabolic conditions over time.

Substantial weight loss in 10 children led to a significant (P < .05) decrease in A-FABP levels in contrast to the 20 children without change of weight status. In cross-sectional as well as longitudinal analyses, A-FABP levels were related to weight status and leptin levels.

In a study involving HIV-infected individuals, patients in the highest quartile of FABP4 presented a six-fold increased odds ratio for metabolic syndrome and a three-fold increased odds for lipodistrophy, adjusted by age, sex, bodymass index and the antiretroviral therapy. FABP4 is a strong plasma marker of metabolic disturbances in HIV-infected patients, and therefore, could serve to guide therapeutic intervention in this group of patients.

High FABP4 plasma concentrations are associated with high plasma creatinine and low MDRD-GFR in patients with type 2 diabetes even in the absence of microalbuminuria or clinically relevant alterations of creatinine and MDRDGFR values. FABP4 concentrations should be taken into consideration as an early marker of kidney damage in patients with type 2 diabetes.

A-FABP is an independent determinant of carotid atherosclerosis in women, but not in men. This gender difference may be attributed to the lower serum A-FABP levels in men, and the effect of other risk factors, such as smoking, among males.

Catalog Number	Species	Analyte	Assay	Regulatory	Format
RD191036200R	Human	Adipocyte Fatty Acid Binding Protein	Sandwich ELISA, Biotin-labelled antibody	RUO	96 wells (1 kit)
RD291036200R	Mouse	Adipocyte Fatty Acid Binding Protein	Sandwich ELISA, Biotin-labelled antibody	RUO	96 wells (1 kit)

categories: Animal studies, Energy metabolism and body weight regulation