Type 2 diabetes-associated fatty acid binding protein 2 promoter haplotypes are differentially regulated by GATA factors

Abstract

The human intestinal fatty acid binding protein 2 (FABP2) mediates fat absorption by binding and intracellular trafficking of long-chain free fatty acids. Studies with knockout mice and association analysis of polymorphisms revealed that FABP2 is a susceptibility gene for type 2 diabetes (noninsulin dependent diabetes mellitus [NIDDM]) and related traits. Relevant FABP2 promoter polymorphisms c.-80_-79insT (rs5861422), c.-136_-132delAGTAG (rs5861423), c.-168_-166delAAGinsT (rs1973598), c.-260G>A (rs6857641), c.-471G>A (rs2282688), and c.-778G>T (rs10034579) result in two haplotypes A and B, whereby B possesses two- to three-fold lower transcriptional activity than A. We show in luciferase reporter gene assays by a series of chimeric FABP2 promoter constructs in intestinal Caco-2 cells that polymorphism c.-80_-79insT essentially determines different activities of the FABP2 promoter. In accordance, in electrophoretic mobility shift assays (EMSAs), transcriptional factors GATA-5 and -6 bind with higher binding affinities to the FABP2 promoter region containing the -80A allele compared to B. As functional consequence, haplotype A is twice as much more activated by GATA factors than haplotype B in liver Huh7 cells. Additionally, a construct bearing the -80B allele in the background of haplotype A reversed the activity from A to B. Thus, the GATA mediated differential activation of FABP2 haplotypes depends on polymorphism c.-80_-79insT. This provides the molecular basis for the variant specific transcriptional regulation of the diabetes type 2-associated FABP2 gene.

Evaluation of FABP2 as candidate gene for a fatty acid composition QTL in porcine chromosome 8

“…(2007) have shown that this variation interacts with the association of the human FABP2:p.Ala54Thr polymorphism. Very recently, Klapper et al . (2008) have shown that GATA factors regulate this promoter variant‐specific transcription rate in the human FABP2 gene, providing a molecular basis for the expression differences among promoter genotypes.…”

“…Damcott et al (2003) and Formanack and Baier (2004) found that nucleotide variation in the promoter of the human FABP2 gene influences its transcription rate and, more recently, Helwig et al (2007) have shown that this variation interacts with the association of the human FABP2:p.Ala54Thr polymorphism. Very recently, Klapper et al (2008) have shown that GATA factors regulate this promoter variant-specific transcription rate in the human FABP2 gene, providing a molecular basis for the expression differences among promoter genotypes. Thus, although the estimated QTL position suggests that the causal factor would be located within the S0144-SW61 marker interval, it cannot be ruled out that a polymorphism in the promoter region of the porcine FABP2 gene, rather than a structural mutation, could be involved in the QTL.…”

Transcriptional regulation of the fatty acid binding protein 2 (FABP2) gene by the hepatic nuclear factor 1 alpha (HNF-1α)

“…More recently, we have shown that FABP2 is regulated by HNF-4α and GATA factors (Klapper et al, 2007b), that are key regulators of intestinal differentiation processes. As described on liver and intestinal expressed fatty acid binding protein FABP1, LPH and SI promoters, HNF-1α co-operates with these factors (Krasinski et al, 2001;Boudreau et al, 2002;van Wering et al, 2002;Divine et al, 2004;van Wering et al, 2004;Rowley et al, 2006) and is also involved in developmental expression of intestinal genes (Bosse et al, 2007).…”

Molecularization in nutritional science: A view from philosophy of science

“…In view of the normative postulate outlined above, we would rather maintain that basic research in nutritional science should address all biopsychosocial aspects of nutrition [17]. Examples of basic research oriented questions in nutritional science may be: Biological: What is the role of the intestinal fatty acid binding protein in fat assimilation [81] and how its regulation can be characterized [82][83][84][85]? Psychological: How do cognitive conditions influence the selection of food [86]?…”