Disease relevance of Fabp1

• Concomitantly, a 6.9-fold induction of liver fatty acid binding protein (L-FABP) expression is observed in comparison to wild-type animals fed standard chow, possibly mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha) [1].
• In control-fed mice, L-FABP gene ablation alone induced hepatic cholesterol accumulation (2.6-fold), increased bile acid levels, and increased body weight gain (primarily as fat tissue mass) [2].
• Although expression of sterol carrier protein (SCP)-2, SCP-x, or liver FABP (L-FABP) in transfected L cells reduced [(3)H]phytanic acid uptake (57-87%) and lipid accumulation (21-27%), nevertheless [(3)H]phytanic acid oxidation was inhibited (74-100%) and phytanic acid toxicity was enhanced in the order L-FABP >> SCP-x > SCP-2 [3].
• CONCLUSIONS: A marked decrease in PPAR alpha expression may be important for changed gene expression, e.g. LFABP, and metabolic changes, such as hypoglycemia, during liver regeneration [4].
• We suggest that L-Fabp(-/-) mice are protected against Western diet-induced obesity and hepatic steatosis through a series of adaptations in both hepatic and extrahepatic energy substrate use [5].

High impact information on Fabp1

• To determine whether the slowed migration was a direct effect of forced expression of E-cadherin or a secondary effect of reduced crypt cell production, another Fabp promoter was used to restrict overproduction of E-cadherin to the villus epithelium of transgenic mice [6].
• Transgenes consisting of segments of the rat liver fatty acid-binding protein (L-FABP) gene's 5' non-transcribed domain linked to the human growth hormone (hGH) gene (minus its regulatory elements) have provided useful tools for analyzing the mechanisms that regulate cellular and spatial differentiation of the continuously renewing gut epithelium [7].
• Immunocytochemical analysis of isografts harvested 4-6 wk after implantation revealed that activation of the intact endogenous mouse L-FABP gene (fabpl) in differentiating enterocytes is perfectly recapitulated as these cells are translocated along the crypt-to-villus axis [7].
• In the present study, we have used immunocytochemical techniques to map the distribution of enteroendocrine cells in the normal adult mouse gut and to characterize those that synthesize L-FABP [8].
• Young (5-7 weeks) mice containing a L-FABP (-4000 to +21)/hGH transgene also demonstrated inappropriate expression of the transgene in most proximal colonic crypts [9].

Chemical compound and disease context of Fabp1

• Although liver fatty acid binding protein (L-FABP) is known to bind not only long chain fatty acid (LCFA) but also long chain fatty acyl CoA (LCFA-CoA), the physiological significance of LCFA-CoA binding has been questioned and remains to be resolved [10].
• In contrast, liver fatty acid binding protein (L-FABP) revealed a modest (2-fold) stimulatory effect on sterol transfer only between PM-MITO and MICRO-MICRO [11].
• Although liver fatty acid binding protein (L-FABP) is known to enhance uptake and esterification of straight-chain fatty acids such as palmitic acid and oleic acid, its effects on oxidation and further metabolism of branched-chain fatty acids such as phytanic acid are not completely understood [12].

Biological context of Fabp1

• Linkage of the murine transforming growth factor alpha gene with Igk, Ly-2, and Fabp1 on chromosome 6 [13].
• Finally to test in vitro whether this induction is conferred by phytanic acid, we cotransfected HepG2 cells with an expression plasmid for murine PPARalpha and a CAT-reporter gene with 176 bp of the murine L-FABP promoter, containing the peroxisome proliferator responsive element (PPRE) [1].
• Although liver fatty acid binding protein (L-FABP) is postulated to influence cholesterol homeostasis, the physiological significance of this hypothesis remains to be resolved [2].
• These results suggest that under fasting conditions, hepatic L-FABP contributes to hepatic LCFA oxidation and ketogenesis by a nontranscriptional mechanism, whereas L-FABP can activate ketogenic gene expression in fed mice [14].
• Although liver fatty acid-binding protein (L-FABP) is an important binding site for various hydrophobic ligands in hepatocytes, its in vivo significance is not understood [15].

Anatomical context of Fabp1

• Then the increase of the in vivo phytanic acid concentration by phytol feeding to mice results in a 4-fold induction of L-FABP expression in liver, which is in the order of that attained with bezafibrate, a known peroxisome proliferator [1].
• Cytosolic transport of phytanic acid to either peroxisomal membranes or to the nucleus for activation of PPARalpha may be mediated by L-FABP, which gives rise to the question whether phytanic acid is a transactivator of this protein [1].
• Immunofluorescence colocalization showed that liver fatty acid-binding protein (L-FABP; binds LCFA-CoA as well as LCFA) significantly colocalized with PPARalpha in nuclei of transfected L-cell fibroblasts [16].
• L-FABP overexpression selectively increased the targeting of BODIPY-C16-S-S-CoA by 1.9- and 2.7-fold into the nuclear membrane and nucleoplasm, respectively [16].
• L-FABP is exclusively expressed in alveolar macrophages within the myeloid lineage: evidence for a PPARalpha-independent expression [17].

Associations of Fabp1 with chemical compounds

• Here we show first that phytanic acid binds to recombinant L-FABP with high affinity [1].
• This issue was addressed by examining the response of young (7 wk) female mice to L-FABP gene ablation and a cholesterol-rich diet [2].
• In contrast, high-affinity LCFA-CoA binding was absent from Fraction III of L-FABP (-/-) mice [10].
• A cis-parinaric acid displacement assay showed that L-FABP bound BODIPY-C12 and BODIPY-C16 with K(i)s of 10.1 +/- 2.5 and 20.7 +/- 1.5 nM, respectively, in the same range as naturally occurring LCFAs [16].
• Nevertheless, the soluble fraction from livers of L-FABP (-/-) mice bound 95% less radioactive oleoyl-CoA than wild-type L-FABP (+/+) mice [10].

Physical interactions of Fabp1

• In contrast to the cultured cell systems, our in vivo DNA electroporation method showed that PPARalpha binding to the promoter is necessary but not sufficient for PPARalpha ligand-dependent transcriptional activation of the L-FABP gene in vivo [18].

Regulatory relationships of Fabp1

• These findings demonstrate that PPARdelta can act as a fibrate/FA-activated receptor in tissues in which it is highly expressed and that L-FABP is a PPARdelta target gene in the small intestine [19].
• Liver fatty acid binding protein (LFABP) is an abundant protein in liver cytosol whose expression is regulated by PPAR alpha [4].
• Thus, TGF beta 1 appears to regulate the expression of L-FABP and I-FABP in the liver and the proximal intestine, respectively [20].

Other interactions of Fabp1

• These effects differed markedly from those of [(3)H]palmitic acid, whose uptake, oxidation, and induction of lipid accumulation were not reduced by L-FABP, SCP-2, or SCP-x expression [3].
• Three genes are shown to be closely linked to the Lc locus, and the map order cen-Cpa-Npy-Cbl-1-Lc-Igk, Fabpl-Pcp-1 is determined [21].
• To explore a possible cause for this gender dimorphic effect, we examined the changes in expression of genes that encode liver fatty acid binding protein (L-FABP) and ileal lipid binding protein in the small intestine resulting from I-FABP deficiency [22].
• Thus, male and female mice clearly respond differently to the loss of I-FABP from the small intestine but the observed changes in the abundance of L-FABP and ilbp protein do not readily account for this phenomenon [22].
• Fatty acid synthase expression was also increased in the skeletal muscle of L-Fabp(-/-) mice [5].

Analytical, diagnostic and therapeutic context of Fabp1

• Finally, solid-phase extraction and HPLC analysis revealed that, depending on the fatty acid content of the culture medium, L-FABP expression also increased the cellular LCFA-CoA pool size and altered the LCFA-CoA acyl chain composition [16].
• The intracellular LCFA-CoA binding protein fraction (Fraction III) from wild-type L-FABP (+/+) mice, isolated by gel permeation chromatography of liver soluble proteins, exhibited one high-affinity binding and several low-affinity binding sites for cis-parinaroyl-CoA, a naturally occurring fluorescent LCFA-CoA [10].
• The 90-kDa protein also binds to an element in the matrix metalloproteinase-2 gene that functions as an enhancer in renal cells, shares sequence homology with the heptad, and generates similar-sized complexes in gel mobility shift assays as the Fabpl repeat [23].
• In this case, LFABP mRNA levels decreased more slowly after partial hepatectomy than in rats [4].
• Stable transfectant cell lines were selected and expression of L-FABP determined using Western blot analysis [24].

References