Disease relevance of Fabp5

• Role of the fatty acid binding protein mal1 in obesity and insulin resistance [1].
• Differential screening of cDNA libraries from chemically induced malignant mouse skin squamous cell carcinomas (SCCs) identified sequences, including one called mal1, that were up-regulated in their expression at both the benign papilloma and the malignant SCC stages during tumor development [2].
• In animals lacking the adipocyte/macrophage FABP isoforms aP2 and mal1, there is strong protection against diet-induced obesity, insulin resistance, type 2 diabetes, fatty liver disease, and hypercholesterolemic atherosclerosis [3].
• The mal1 plasmid cDNA clone was used to screen lambda phage cDNA libraries made from chemically induced papillomas and SCCs [2].
• A recombinant adenovirus was constructed (expressing green fluorescent protein [GFP] under the control of the strong cytomegalovirus [CMV] promoter and a luciferase reporter gene under the control of the weak adipocyte promoter keratinocyte lipid-binding protein [KLBP/FABP5]) and incubated with primary adipocytes from C57BL/6J mice [4].

High impact information on Fabp5

• However, in the presence of 10 microm oleate, A-FABP and E-FABP each bound to HSL with high affinity (Kd of 0.5 and 3 nM, respectively) in a approximately 1:1 molar stoichiometry, whereas liver FABP and intestinal FABP did not exhibit any association [5].
• Adipocytes isolated from mal1-deficient mice also exhibited enhanced insulin-stimulated glucose transport capacity [1].
• Hence, our results demonstrate that mal1 modulates adipose tissue function and contributes to systemic glucose metabolism and constitutes a potential therapeutic target in insulin resistance [1].
• In contrast, mice expressing high levels of mal1 in adipose tissue display reduced systemic insulin sensitivity [1].
• Here, we report the generation of mice with targeted null mutations in the mal1 gene as well as transgenic mice overexpressing mal1 from the aP2 promoter/enhancer to address the role of this FABP in metabolic regulation in the presence or absence of obesity [1].

Biological context of Fabp5

• Fluorescence in-situ hybridization identified the murine KLBP gene as the fourth FABP gene on chromosome 3, along with myelin P2, ALBP, and intestinal FABP [6].
• Similar to the other FABP genes, the functional KLBP gene contains four exons separated by three introns and maintains the conservation of size and placement of each exon [6].
• The keratinocyte lipid-binding protein (KLBP) is a member of a large multigene family of intracellular fatty-acid-binding proteins [6].
• The fatty acid binding proteins aP2 (fatty acid binding protein [FABP]-4) and mal1 (FABP5) are closely related and both are expressed in adipocytes [1].
• Stabilization of LTA(4) was examined when arachidonic acid was present to compete with LTA(4) for the binding site on E-FABP [7].

Anatomical context of Fabp5

• We present evidence that endogenous ACBP, ALBP, and KLBP not only localize to the cytoplasm but also exhibit a prominent nuclear localization in 3T3-L1 adipocytes [8].
• Evaluation of retinal pigment epithelial cell extracts derived from E-FABP null mice by two-dimensional gel electrophoresis using anti-4-HNE antibodies revealed increased modification in the null cells relative to those from wild type cells [9].
• It appears that the small amount of E-FABP expressed in MCF7 cells fulfils the need of the cells for a cytosolic fatty acid carrier under culture conditions and that even high concentrations of another FABP do only slightly increase the uptake due to limitations of fatty acid transport through the plasma membrane or of metabolism [10].
• The possible natures of these cells immunoreactive for E-FABP are discussed in view of a subpopulation of endothelial cells or the dendritic cells of antigen-presenting property [11].
• On the other hand, epidermal-type fatty acid binding protein (E-FABP) is localized in two discrete cells in the adrenal gland: the one is a subpopulation of intra-adrenal macrophages which are intensely immunoreactive for F4/80, a marker of macrophages, and are rich in pleomorphic lysosomes [11].

Associations of Fabp5 with chemical compounds

• As measured by guanidinium hydrochloride denaturation, the stability of ALBP/aP2 is nearly 3 kcal/mol greater than that of KLBP [12].
• ALBP/aP2 and KLBP exhibit similar binding affinities for most long-chain fatty acids; however, ALBP/aP2 exhibits a two to three-fold increased affinity for myristic, palmitic, oleic and linoleic acids, the predominant fatty acids of adipocytes [12].
• 4-HNE-modified E-FABP was more stable than unmodified E-FABP to chemical denaturation by guanidine hydrochloride, as assessed by changes in intrinsic tryptophan fluorescence [9].
• When E-FABP is not saturated with arachidonate, FABP can still stabilize LTA(4) [7].
• Several lipoxygenase products, including 5-hydroxyeicosatetraenoic acid, 5,6-dihydroxyeicosatetraenoic acid, and leukotriene B(4), were found to have no effect on the stability of LTA(4) induced by E-FABP even when present at concentrations 3-fold higher than LTA(4) [7].

Other interactions of Fabp5

• This indicated that E-FABP and/or H-FABP are involved in the mediation of DPPC synthesis in wt TII cells [13].
• We tested the hypothesis that combined aP2 and mal1 deficiency would produce synergistic effects on metabolism and reduce atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice [14].
• In vitro translation of mal1 RNA yielded a polypeptide of the predicted size of 15 kDa that was immunoprecipitable with an anti-rat liver fatty acid-binding protein antiserum [2].
• These results indicate that E-FABP is a molecular target for 4-HNE modification and the hypothesis that E-FABP functions as an antioxidant protein by scavenging reactive lipids through covalent modification of Cys-120 [9].
• The non-tumor-promoting hyperplastic agent, ethylphenyl propiolate (EPP), applied to the skin at a hyperplastic dose level did not enhance the expression of the mal 4 or transin sequences in the epidermis and had only a slight enhancing effect on the levels of mal 1 and mal 2 transcripts in the epidermis [15].

Analytical, diagnostic and therapeutic context of Fabp5

• RT-PCR on primary adipocyte RNA demonstrated expression of this KLBP gene by amplification of intron 3 from the primary transcript [6].
• Based on the sequence analysis and antigenic properties of mal1, we conclude that it encodes a novel member of the lipid-binding protein family [2].
• 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 [16].
• The localization of epidermal-type fatty acid binding protein (E-FABP) in the mature mouse ovary was examined by immuno-light and electron microscopy [17].

References