The Effects of Retinol on Postprandial Parameters in Men with Different FABP2 Promoter Haplotypes

Abstract

The fatty acid binding protein 2 (FABP2) mediates the intestinal uptake of fatty acids. We and others have identified six FABP2 promoter polymorphisms which result in two haplotypes, A and B. Reporter-gene assays indicated different activity in FABP2 promoter alleles A and B and different responsiveness to PPAR ligands. In silico analysis revealed different putative binding sites in FABP2 haplotypes for retinoid-dependent transcription factors. Therefore, we assumed that retinol supplementation may effect postprandial fat uptake differently in men with FABP2 promoter haplotype A and B. To test this hypothesis, we administered 5000 I.U. retinol/day for 8 weeks to 19 homozygotes for AA and 21 homozygotes for BB and assessed the alteration of postprandial triglycerides during this intervention. FABP2 genotype groups did not significantly differ in anthropometric and laboratory parameters. The alteration of postprandial triglycerides did not differ significantly between genotypes during intervention. This also held true after adjustment for BMI. Furthermore, in a subgroup which had a combination of promoter and common exon polymorphism, the alteration of the postprandial triglycerides did not differ between genotypes. In conclusion, the postprandial triglyceride metabolism of FABP2 promoter AA and BB did not respond differently to retinol administration even though in silico analysis suggested this.

gene-nutrient interaction - retinol - fatty acid binding protein - postprandial triglyceride metabolism

References

• 1 Sweetser DA, Heuckeroth RO, Gordon JI. The metabolic significance of mammalian fatty-acid-binding proteins: abundant proteins in search of a function.  Annu Rev Nutr. 1987;  7 337-359
• 2 Lowe JB, Sacchettini JC, Laposata M, McQuillan JJ, Gordon JI. Expression of rat intestinal fatty acid-binding protein in Escherichia coli. Purification and comparison of ligand binding characteristics with that of Escherichia coli-derived rat liver fatty acid-binding protein.  J Biol Chem. 1987;  262 5931-5937
• 3 Sweetser DA, Birkenmeier EH, Klisak IJ, Zollman S, Sparkes RS, Mohandas T, Lusis AJ, Gordon JI. The human and rodent intestinal fatty acid binding protein genes. A comparative analysis of their structure, expression, and linkage relationships.  J Biol Chem. 1987;  262 16060-16071
• 4 Baier LJ, Bogardus C, Sacchettini JC. A polymorphism in the human intestinal fatty acid binding protein alters fatty acid transport across Caco-2 cells.  J Biol Chem. 1996;  271 10892-10896
• 5 Baier LJ, Sacchettini JC, Knowler WC, Eads J, Paolisso G, Tataranni PA, Mochizuki H, Bennett PH, Bogardus C, Prochazka M. An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance.  J Clin Invest. 1995;  95 1281-1287
• 6 Agren JJ, Valve R, Vidgren H, Laakso M, Uusitupa M. Postprandial lipemic response is modified by the polymorphism at codon 54 of the fatty acid-binding protein 2 gene.  Arterioscler Thromb Vasc Biol. 1998;  18 1606-1610
• 7 Agren JJ, Vidgren HM, Valve RS, Laakso M, Uusitupa MI. Postprandial responses of individual fatty acids in subjects homozygous for the threonine- or alanine-encoding allele in codon 54 of the intestinal fatty acid binding protein 2 gene.  Am J Clin Nutr. 2001;  73 31-35
• 8 Dworatzek PD, Hegele RA, Wolever TM. Postprandial lipemia in subjects with the threonine 54 variant of the fatty acid-binding protein 2 gene is dependent on the type of fat ingested.  Am J Clin Nutr. 2004;  79 1110-1117
• 9 Weiss EP, Brown MD, Shuldiner AR, Hagberg JM. Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects.  Physiol Genomics. 2002;  10 145-157
• 10 Berthier MT, Couillard C, Prud'homme D, Nadeau A, Bergeron J, Tremblay A, Despres JP, Vohl MC. Effects of the FABP2 A54T mutation on triglyceride metabolism of viscerally obese men.  Obes Res. 2001;  9 668-675
• 11 Geschonke K, Klempt M, Lynch N, Schreiber S, Fenselau S, Schrezenmeir J. Detection of a promoter polymorphism in the gene of intestinal fatty acid binding protein (I-FABP).  Ann N Y Acad Sci. 2002;  967 548-553
• 12 Damcott CM, Feingold E, Moffett SP, Barmada MM, Marshall JA, Hamman RF, Ferrell RE. Variation in the FABP2 promoter alters transcriptional activity and is associated with body composition and plasma lipid levels.  Hum Genet. 2003;  112 610-616
• 13 Formanack ML, Baier LJ. Variation in the FABP2 promoter affects gene expression: implications for prior association studies.  Diabetologia. 2004;  47 349-351
• 14 Helwig U, Rubin D, Klapper M, Li Y, Nothnagel M, Foelsch UR, Doering F, Schreiber S, Schrezenmeir J. Interfering impact of exon and promoter gene variability of fatty acid binding protein 2 on postprandial lipemia and insulin sensitivity.  Metabolism. , in press
• 15 Green RP, Cohn SM, Sacchettini JC, Jackson KE, Gordon JI. The mouse intestinal fatty acid binding protein gene: nucleotide sequence, pattern of developmental and regional expression, and proposed structure of its protein product.  DNA Cell Biol. 1992;  11 31-41
• 16 Rottman JN, Gordon JI. Comparison of the patterns of expression of rat intestinal fatty acid binding protein/human growth hormone fusion genes in cultured intestinal epithelial cell lines and in the gut epithelium of transgenic mice.  J Biol Chem. 1993;  268 11994-12002
• 17 Cohn SM, Simon TC, Roth KA, Birkenmeier EH, Gordon JI. Use of transgenic mice to map cis-acting elements in the intestinal fatty acid binding protein gene (Fabpi) that control its cell lineage-specific and regional patterns of expression along the duodenal-colonic and crypt-villus axes of the gut epithelium.  J Cell Biol. 1992;  119 27-44
• 18 Schachtrup C, Emmler T, Bleck B, Sandqvist A, Spener F. Functional analysis of peroxisome-proliferator-responsive element motifs in genes of fatty acid-binding proteins.  Biochem J. 2004;  382 239-245
• 19 Glass CK, Rose DW, Rosenfeld MG. Nuclear receptor coactivators.  Curr Opin Cell Biol. 1997;  9 222-232
• 20 Kliewer SA, Umesono K, Heyman RA, Mangelsdorf DJ, Dyck JA, Evans RM. Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling.  Proc Natl Acad Sci USA. 1992;  89 1448-1452
• 21 Arceci RJ, King AA, Simon MC, Orkin SH, Wilson DB. Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart.  Mol Cell Biol. 1993;  13 2235-2246
• 22 Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling.  J Clin Invest. 2006;  116 607-614
• 23 Vossen C, Erard M. Down-regulation of nuclear receptor DNA-binding activity by nitric oxide-HNF4 as a model system.  Med Sci Monit. 2002;  8 RA217-RA220
• 24 Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism.  Endocr Rev. 1999;  20 649-688
• 25 Rubin D, Helwig U, Foelsch UR,  , Nothnagel M, Schrezenmeir J. Postprandial characterisation of a population based random sample and association with the metabolic syndorme - Metabolic Interaction Count Kill (MICK).  , Submitted
• 26 Lahti-Koski M, Pietinen P, Mannisto S, Vartiainen E. Trends in waist-to-hip ratio and its determinants in adults in Finland from 1987 to 1997.  Am J Clin Nutr. 2000;  72 1436-1444
• 27 WHO . Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee.  World Health Organ Tech Rep Ser. 1995;  854 1-452
• 28 Schrezenmeir J, Weber P, Probst R, Biesalski HK, Luley C, Prellwitz W, Krause U, Beyer J. Postprandial pattern of triglyceride-rich lipoprotein in normal-weight humans after an oral lipid load: exaggerated triglycerides and altered insulin response in some subjects.  Ann Nutr Metab. 1992;  36 186-196
• 29 Hampe J, Shaw SH, Saiz R, Leysens N, Lantermann A, Mascheretti S, Lynch NJ, MacPherson AJ, Bridger S, van Deventer S, Stokkers P, Morin P, Mirza MM, Forbes A, Lennard-Jones JE, Mathew CG, Curran ME, Schreiber S. Linkage of inflammatory bowel disease to human chromosome 6p.  Am J Hum Genet. 1999;  65 1647-1655
• 30 Deutsche Gesellschaft für Ernährung .title: Referenzwerte für die Nährstoffzufuhr. Frankfurt am Main: Umschau/Braus 2000: 69-77
• 31 Gerlach T, Biesalski HK, Bassler KH. [Serum vitamin A determinations and their value in determining vitamin A status].  Z Ernahrungswiss. 1988;  27 57-70

1 U H. and D R. contributed equally to the study

Correspondence