Alternative titles; symbols
HGNC Approved Gene Symbol: FABP4
Cytogenetic location: 8q21.13 Genomic coordinates (GRCh38): 8:81,478,419-81,483,233 (from NCBI)
FABP4, or AP2, functions as a cytosolic lipid chaperone in macrophages and is involved in regulating macrophage endoplasmic reticulum (ER) stress (Erbay et al., 2009).
Baxa et al. (1989) purified human adipocyte FABP (called H-ALBP by them) from normal subcutaneous adipose tissue. The 15-kD protein composed about 1% of total cytosolic protein in human adipose tissue. They also cloned a full-length cDNA that encodes a predicted 132-amino acid polypeptide. Baxa et al. (1989) also identified a consensus tyrosyl kinase phosphorylation site.
Shum et al. (2006) generated a gene expression profile of human bronchial epithelial cells (HBEs) upon stimulation with the Th2 cytokine IL4 (147780) and found that the FABP4 protein is expressed in HBEs and is strongly upregulated by both IL4 and IL13 (147683) and downregulated by IFN-gamma (147570), suggesting a role in allergic airway inflammation.
Furuhashi et al. (2007) demonstrated that an orally active small-molecule inhibitor of AP2 is an effective therapeutic agent against severe atherosclerosis (see 108725) and type 2 diabetes (see 125853) in mouse models. In macrophage and adipocyte cell lines with or without AP2, they also showed the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Furuhashi et al. (2007) concluded that their findings demonstrated that targeting AP2 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.
Using mouse macrophage cell lines and knockout mouse models, Erbay et al. (2009) identified Ap2 as the predominant regulator of toxic lipid-induced ER stress in macrophages. Ap2 expression was directly related to lipid-induced ER stress, and palmitate or free cholesterol failed to induce ER stress in Ap2 -/- macrophages. Early-stage atherosclerotic plaques from Apoe (107741) -/- mice showed induction of ER stress, whereas lesions from Ap2 -/- Apoe -/- double-knockout mice showed reduced ER stress and reduced number of apoptotic macrophages. Erbay et al. (2009) concluded that AP2 has a central role in modulating the lipid-induced ER stress response.
Tissue-resident memory T (TRM) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. Pan et al. (2017) demonstrated that mouse CD8+ TRM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including FABP4 and FABP5 (605168). They further showed that T cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8+ TRM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (TCM) cells in lymph nodes. In vitro, CD8+ TRM cells, but not CD8+ TCM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8+ TRM cells. The persistence of CD8+ TRM cells in the skin was strongly diminished by inhibition of mitochondrial FFA beta-oxidation in vivo. Moreover, skin CD8+ TRM cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8+ TRM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8+ TRM cells in normal and psoriatic skin. Pan et al. (2017) concluded that these results suggested that FABP4 and FABP5 have a critical role in the maintenance, longevity, and function of CD8+ TRM cells, and suggested that CD8+ TRM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.
Prinsen et al. (1997) stated that the FABP4 gene is organized into 4 exons.
By PCR of a somatic cell hybrid panel and fluorescence in situ hybridization, Prinsen et al. (1997) mapped the FABP4 gene to 8q21.
Tuncman et al. (2006) identified a -87T-C transition in the 5-prime promoter region of the FABP4 gene and demonstrated decreased adipose tissue FABP4 expression due to alteration of the CAAT box/enhancer-binding protein binding and reduced transcriptional activity of the FABP4 promoter. In population genetic studies with 7,899 participants, individuals carrying the -87T-C polymorphism had lower serum triglyceride levels and significantly reduced risk for coronary heart disease and type 2 diabetes compared with subjects homozygous for the wildtype allele.
Hotamisligil et al. (1996) noted that fatty acid-binding proteins are small cytoplasmic proteins that are expressed in a highly tissue-specific manner. They investigated the function of adipocyte fatty acid-binding proteins by creating a null mutation in the murine aP2 gene by homologous recombination. The aP2-deficient mice were developmentally and metabolically normal. Hotamisligil et al. (1996) placed the aP2-deficient mice on a high-fat, high-caloric diet (3490 kcal per kg body weight, with 40% of the total calories from fat). On this diet, control mice and aP2 -/- mice developed obesity, and the total weight gain in aP2 -/- mice was higher than that in wildtype controls. Notably, the aP2 -/- mice did not develop insulin resistance or diabetes, and they also failed to express tumor necrosis factor-alpha (191160) in adipose tissue. Hotamisligil et al. (1996) concluded that aP2 is central to the pathway that links obesity to insulin resistance.
Shum et al. (2006) examined Fabp4-deficient mice in a model of allergic airway inflammation and found that infiltration of leukocytes, especially eosinophils, into the airways was highly dependent on Fabp4 function. T-cell priming was unaffected by Fabp4 deficiency, suggesting that Fabp4 was acting locally within the lung, and analysis of bone marrow chimeras implicated nonhematopoietic cells, most likely bronchial epithelial cells, as the site of action of Fabp4 in allergic airway inflammation. Shum et al. (2006) concluded that FABP4 regulates allergic airway inflammation and may provide a link between fatty acid metabolism and asthma.
Baxa, C. A., Sha, R. S., Buelt, M. K., Smith, A. J., Matarese, V., Chinander, L. L., Boundy, K. L., Bernlohr, A. Human adipocyte lipid-binding protein: purification of the protein and cloning of its complementary DNA. Biochemistry 28: 8683-8690, 1989. [PubMed: 2481498] [Full Text: https://doi.org/10.1021/bi00448a003]
Erbay, E., Babaev, V. R., Mayers, J. R., Makowski, L., Charles, K. N., Snitow, M. E., Fazio, S., Wiest, M. M., Watkins, S. M., Linton, M. F., Hotamisligil, G. S. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nature Med. 15: 1383-1391, 2009. Note: Erratum: Nature Med. 16: 237 only, 2010. [PubMed: 19966778] [Full Text: https://doi.org/10.1038/nm.2067]
Furuhashi, M., Tuncman, G., Gorgun, C. Z., Makowski, L., Atsumi, G., Vaillancourt, E., Kono, K., Babaev, V. R., Fazio, S., Linton, M. F., Sulsky, R., Robl, J. A., Parker, R. A., Hotamisligil, G. S. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447: 959-965, 2007. [PubMed: 17554340] [Full Text: https://doi.org/10.1038/nature05844]
Hotamisligil, G. S., Johnson, R. S., Distel, R. J., Ellis, R., Papaioannou, V. E., Spiegelman, B. M. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274: 1377-1379, 1996. [PubMed: 8910278] [Full Text: https://doi.org/10.1126/science.274.5291.1377]
Pan, Y., Tian, T., Park, C. O., Lofftus, S. Y., Mei, S., Liu, X., Luo, C., O'Malley, J. T., Gehad, A., Teague, J. E., Divito, S. J., Fuhlbrigge, R., Puigserver, P., Krueger, J. G., Hotamisligil, G. S., Clark, R. A., Kupper, T. S. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543: 252-256, 2017. [PubMed: 28219080] [Full Text: https://doi.org/10.1038/nature21379]
Prinsen, C. F. M., de Bruijn, D. R. H., Merkx, G. F. M., Veerkamp, J. H. Assignment of the human adipocyte fatty acid-binding protein gene (FABP4) to chromosome 8q21 using somatic cell hybrid and fluorescence in situ hybridization techniques. Genomics 40: 207-209, 1997. [PubMed: 9070949] [Full Text: https://doi.org/10.1006/geno.1996.4534]
Shum, B. O. V., Mackay, C. R., Gorgun, C. Z., Frost, M. J., Kumar, R. K., Hotamisligil, G. S., Rolph, M. S. The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation. J. Clin. Invest. 116: 2183-2192, 2006. [PubMed: 16841093] [Full Text: https://doi.org/10.1172/JCI24767]
Tuncman, G., Erbay, E., Hom, X., De Vivo, I., Campos, H., Rimm, E. B., Hotamisligil, G. S. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc. Nat. Acad. Sci. 103: 6970-6975, 2006. [PubMed: 16641093] [Full Text: https://doi.org/10.1073/pnas.0602178103]