Disease relevance of Fabp3

• H-FABP deficiency is only incompletely compensated, however, causing acute exercise intolerance and, at old age, a localized cardiac hypertrophy [1].
• In conclusion, a partial reduction in H-FABP protein normalizes fasting glucose levels and improves whole-body insulin sensitivity in HFD-fed mice despite obesity [2].
• During exercise, blood glucose (mM) increased in WT (11.7 +/- 0.8) and H-FABP(+/-) (12.6 +/- 0.9) mice, whereas H-FABP(-/-) mice developed overt hypoglycemia (4.8 +/- 0.8) [3].
• Fatty acid metabolism in human breast cancer cells (MCF7) transfected with heart-type fatty acid binding protein [4].
• A mammary-derived growth inhibitor (MDGI) inhibits the resumption of growth of stationary Ehrlich ascites carcinoma (EAC) cells in vitro [5].

High impact information on Fabp3

• The heart fatty acid-binding protein (HFABP) is a member of a family of binding proteins with distinct tissue distributions and diverse roles in fatty acid metabolism, trafficking, and signaling [6].
• We used transient and permanent transfections in ventricular myocytes, skeletal myocytes, and nonmyocytic cells to map regulatory elements in the HFABP promoter, and audited results in transgenic mice [6].
• These findings provide a physiological demonstration of a crucial role of H-FABP in uptake and oxidation of LCFAs in cardiac muscle cells and indicate that in H-FABP(-/-) mice the diminished contribution of LCFAs to cardiac energy production is, at least in part, compensated for by an increase in glucose oxidation [7].
• Heart-type fatty acid binding protein (H-FABP), abundantly expressed in cardiac myocytes, has been postulated to facilitate the cardiac uptake of long-chain fatty acids (LCFAs) and to promote their intracellular trafficking to sites of metabolic conversion [7].
• Mice with a disrupted H-FABP gene were recently shown to have elevated plasma LCFA levels, decreased cardiac deposition of a LCFA analogue, and increased cardiac deoxyglucose uptake, which qualitatively establishes a requirement for H-FABP in cardiac LCFA utilization [7].

Chemical compound and disease context of Fabp3

• Antiestrogens (tamoxifen and ICI 182780), which are commonly used in breast cancer treatment, stabilize MDGI mRNA [8].

Biological context of Fabp3

• Fabph1 was positioned on chromosome (Chr) 4 using interrelated sequence [9] locus, Fabph-rs1, to Chr 8 [10].
• From a mouse genomic library we isolated and characterized a gene, Fabph1, encoding mammary-derived growth inhibitor (MDGI)/heart fatty-acid-binding protein (H-FABP) [10].
• Exon sequences were identical with a MDGI-encoding cDNA isolated previously from the mammary gland of pregnant mice [10].
• Peroxisome proliferator-activated receptor alpha and its response element are required but not sufficient for transcriptional activation of the mouse heart-type fatty acid binding protein gene [11].
• In addition to this expressed gene, we isolated a related intronless pseudogene, Fabph-ps, with an open reading frame which was highly conserved when compared with Fabph1 [10].
• FABP3 expression enhances brain arachidonic acid uptake and trafficking [9].
• FABP3 expression increases palmitic acid and arachidonic acid uptake and trafficking in heart. In addition, its expression is important for maintaining heart phospholipid mass, including phosphatidylinositol and plasmalogens [12].

Anatomical context of Fabp3

• Analysis by isoelectric focusing of the immunoprecipitated in vitro translation products of lactating bovine mammary gland mRNA did not indicate a protein corresponding to the in vitro translation product of artificial MDGI mRNA [13].
• Expression of heart-type fatty acid binding protein is restricted mainly to the skeletal and cardiac muscles and further regulated by peroxisome proliferator-activated receptor alpha [11].
• The 5'-flanking region of Fabph1 contains putative transcription factor-binding elements which could account for its constitutive expression in muscle tissue, as well as for its developmental stage-dependent expression in mammary epithelium [10].
• In the same way, C2C12 myoblasts transfected with promoter fragments of E-FABP and H-FABP genes containing putative PPREs are also not activated through stimulation of PPARs with bezafibrate applied to the cells [14].
• Since transfer by an aqueous diffusion mechanism would be unaffected by acceptor membrane properties, these studies strengthen the hypothesis that free fatty acid transfer from A- and H-FABP to membranes occurs via a collisional mechanism [15].

Associations of Fabp3 with chemical compounds

• We found that further activation of PPARgamma could 'heal' the E/H-FABP double-ko effect in these TII cells as transport and utilisation of labelled palmitic acid restored a wt phenocopy [16].
• We tested the hypothesis that H-FABP facilitates increases in LCFA flux present in glucose-intolerant states and that a partial reduction in the amount of this protein would compensate for all or part of the impairment [2].
• We, therefore, examined whether the acceptor membrane structure and lipid composition regulate the rate of anthroyloxy-labeled palmitate (2AP) transfer from A- and H-FABP, using a fluorescence resonance energy transfer assay [15].
• In addition, the rate of 2AP transfer from A- and H-FABP was enhanced by unsaturation of the phosphatidylcholine acyl chains and was slowed by the presence of cholesterol or sphingomyelin in the acceptor membranes [15].
• Nevertheless, acrylamide quenching experiments indicate that ffa bound to H-FABP are more accessible to the aqueous environment than are A-FABP-bound ffa.(ABSTRACT TRUNCATED AT 250 WORDS)[17]

Other interactions of Fabp3

• Western blotting and immunofluorescence using monospecific antibodies demonstrated the coexistence of H-FABP and A-FABP in the lactating mammary gland [13].
• This indicated that E-FABP and/or H-FABP are involved in the mediation of DPPC synthesis in wt TII cells [16].
• There were lower concentrations of creatine phosphate (-41%), ATP (-22%), glycogen (-34%), and lactate (-31%) (P < 0.05) in H-FABP-null soleus muscles, but no differences in citrate synthase and beta-3-hydroxyacyl-CoA dehydrogenase activities or in the intramuscular triacylglycerol (TAG) depots [18].
• Although a novel brain-specific fatty acid-binding protein (B-FABP) was recently cloned, the identity of a second fatty acid-binding protein detected with antibodies to the heart (H-FABP) has not been clearly resolved [19].
• MDGI/H-FABP protein was mainly detected in myocardium, skeletal and smooth muscle fibres, lipid and/or steroid synthesising cells (adrenals, Leydig cells, sebaceous glands, lactating mammary gland) and terminally differentiated epithelia of the respiratory, intestinal and urogenital tracts [20].

Analytical, diagnostic and therapeutic context of Fabp3

• Appropriate tissue-specific expression in cell culture and in transgenic mice was dictated by 1.2 kb of the 5'-flanking sequence of FABP3, the HFABP gene [6].
• In Northern blot analysis for other FABPs, the gene expression of heart (H-)-type FABP is specifically elevated in the liver of neonatal heterozygous and homozygous mice, suggesting the functional compensation of H-FABP for E-FABP deficiency during their development [21].
• By enzyme linked immunoassay we now determined the amount of bovine H-FABP in these cells as 638 +/- 80 ng/mg protein and used the transfected cells to study the role of H-FABP in fatty acid metabolism [4].
• In contrast, in resting H-FABP(-/-) cardiac myocytes, glucose oxidation is increased (+80%) to a level that would require electrical stimulation in wild-type cells [7].
• MDGI and an 11 amino acid MDGI-derived conserved C-terminal peptide (P108) inhibits growth of normal mammary epithelial cells in tissue and organ culture, but fails to inhibit proliferation of many breast cancer cell lines in vitro [22].

References