Disease relevance of FABP6

• Transformation of Escherichia coli with the I-15P cDNA resulted in the efficient expression of a protein that was identical to the ileal cytosolic I-15P [1].
• However, when study participants were subgrouped by body weight, ASBT and ILBP protein were 48% and 67% lower in normal weight gallstone carriers than in controls (P < 0.05); similar differences were found for mRNA expression levels [2].
• Subfamily proteins bind retinoids, subfamily II proteins bind bulky ligands, examples are intestinal bile acid binding protein (I-BABP) and liver fatty acid binding protein (L-FABP) which binds 2 ligand molecules, preferably monounsaturated and n-3 fatty acids [3].
• Because bile acids are implicated in the carcinogenesis of colorectal cancer, we evaluated FABP6 expression in colorectal cancer [4].
• CONCLUSIONS: The expression of FABP6 was higher in primary colorectal cancers and adenomas than in normal epithelium, but was dramatically decreased in lymph node metastases, suggesting that FABP6 may play an important role in early carcinogenesis [4].

High impact information on FABP6

• In Caco-2 cells, antisense-mediated knock-down of endogenous familial intrahepatic cholestasis-1 led to up-regulation of apical sodium-dependent bile acid transporter and down-regulation of FXR, ileal lipid-binding protein, and short heterodimer partner mRNA [5].
• Bile acids secreted in the small intestine are reabsorbed in the ileum where they activate the nuclear farnesoid X receptor (FXR), which in turn stimulates expression of the ileal bile acid-binding protein (I-BABP) [6].
• In vitro binding assays reveal that recombinant I-BABP is able to bind 35S-labeled FXR and that chenodeoxycholic acid (CDCA) stimulates this interaction modestly [6].
• In these cells I-BABP localizes predominantly in the cytosol and partially in the nucleus, a distribution that does not shift in response to FXR expression [6].
• Reporter assays using stable HEK293 cell lines expressing I-BABP revealed that I-BABP enhances rather than attenuates FXR activity [6].

Biological context of FABP6

• Northern blot analysis of human I-15P revealed a single transcript only in ileum, however, the reverse-transcription/PCR demonstrated expression in ovary and placenta, but it was much lower than in ileum [1].
• The deduced amino acid sequence of human I-15P showed high similarity to the rat counterpart (78%), mouse ileal lipid-binding protein (80%) and porcine gastrotropin (75%) [1].
• We have isolated a cDNA encoding a human intestinal 15-kDa protein (I-15P) from a human ileal lambda gt 11 cDNA library, using a full-length rat I-15P cDNA [1].
• Human I-15P thus represents a distinctive, confined tissue distribution different from the other FABPs and is expected to serve as a useful cellular marker of terminal ileal enterocytes [7].
• Using the human enterocyte-like Caco-2 cell line, we have recently shown that BAs increased I-BABP gene expression [8].

Anatomical context of FABP6

• A deficiency of the apical sodium bile acid transporter (ASBT) and ileal lipid binding protein (ILBP) in the small intestine may result in bile acid loss into the colon and might promote gallstone formation by reducing the bile acid pool and increasing the amount of hydrophobic bile salts [2].
• To test this hypothesis, protein levels and mRNA expression of ASBT and ILBP were assessed in ileal mucosa biopsies of female gallstone carriers and controls [2].
• PURPOSE: Fatty acid binding protein 6 (FABP6) is a cancer-related protein that acts as an intracellular transporter of bile acid in the ileal epithelium [4].
• EXPERIMENTAL DESIGN: The expression of FABP6 mRNA was evaluated in 78 paired samples of cancer/normal tissue representing colorectal cancer cases, plus 16 adenomas, and 16 metastatic lymph nodes [4].
• To define the functional characteristics of all eight human FABPs, viz. heart (H), brain (B), myelin (M), adipocyte (A), epidermal (E), intestinal (I), liver (L) and ileal lipid-binding protein (I-LBP), we studied their ligand specificity, their conformational stability and their immunological crossreactivity [9].

Associations of FABP6 with chemical compounds

• In vitro binding studies revealed that the bacterially expressed recombinant I-15P showed much lower affinities for palmitate and oleate than L-FABP [1].
• A dramatic drop in I-BABP mRNA levels was observed in mice treated with the BA-binding resin cholestyramine, whereas an increase was found in animals fed with taurocholic acid [8].
• Solution structure of ileal lipid binding protein in complex with glycocholate [10].
• In vivo, human ileal bile acid binding protein (I-BABP) encounters a range of bile salts that vary in the number and position of steroidal hydroxyl groups and the presence and type of side-chain conjugation [11].
• Total cholesterol, LDL cholesterol, and apoB levels were very similar between the GT and GG genotypes; therefore, the GT and GG genotypes were combined as 1 group when the 3 phenotypes were analyzed [12].

Other interactions of FABP6

• Neither ASBT nor ILBP levels differed significantly between gallstone carriers and controls [2].
• In contrast to the I-FABP, L-FABP and I-BABP share several common structural features (shape, size and volume of the hydrophobic pocket) [13].
• Southern blot analysis of genomic DNA from a panel of rodent-human somatic cell hybrids revealed that the human ILBP gene resides on chromosome 5 and is not linked to any other known fatty acid-binding protein family member [14].
• Surprisingly, this compound acts in a gene-selective manner in vivo: it is an agonist on CYP7A1, an antagonist on IBABP, and is neutral on SHP [15].
• Here we report studies of the binding site selectivity of I-BABP for glycocholic (GCA) and glycochenodeoxycholic (GCDA) acids using isotope-enriched bile salts along with two-dimensional heteronuclear NMR methods [11].

Analytical, diagnostic and therapeutic context of FABP6

• Molecular cloning, expression, and characterization of a human intestinal 15-kDa protein [1].
• Using progressive 5' deletions of the hI-BABP promoter and sequence analysis, we identified a putative PPAR-binding site located at the position -198 and -186 upstream of the transcription initiation site [16].
• The level of I-BABP expression was evaluated by Northern and Western blot analyses [17].
• Serum TAP was determined by a standard colorimetric assay, BAP by the methods of lectin precipitation (L-BAP), enzyme immunoassay (E-BAP), and immunoradiometric assay (I-BAP) [18].
• The interaction of I-BABP with nine physiologically relevant derivatives of cholic acid, chenodeoxycholic acid, and deoxycholic acid in their conjugated (glycine and taurine) and unconjugated forms was monitored by isothermal titration calorimetry [19].

References