Limits...
Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics.

Sanderson LM, de Groot PJ, Hooiveld GJ, Koppen A, Kalkhoven E, Müller M, Kersten S - PLoS ONE (2008)

Bottom Line: The effect of dietary fats on human health and disease are likely mediated by changes in gene expression.Interestingly, using Nuclear Receptor PamChip(R) Arrays, fatty acid- and WY14643-induced interactions between PPARalpha and coregulators were found to be highly similar, although several PPARalpha-coactivator interactions specific for WY14643 were identified.We conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARalpha and mimic those of synthetic PPARalpha agonists in terms of regulation of target genes and molecular mechanism.

View Article: PubMed Central - PubMed

Affiliation: Nutrigenomics Consortium, Top Institute (TI) Food and Nutrition, Wageningen, The Netherlands.

ABSTRACT

Background: The effect of dietary fats on human health and disease are likely mediated by changes in gene expression. Several transcription factors have been shown to respond to fatty acids, including SREBP-1c, NF-kappaB, RXRs, LXRs, FXR, HNF4alpha, and PPARs. However, it is unclear to what extent these transcription factors play a role in gene regulation by dietary fatty acids in vivo.

Methodology/principal findings: Here, we take advantage of a unique experimental design using synthetic triglycerides composed of one single fatty acid in combination with gene expression profiling to examine the effects of various individual dietary fatty acids on hepatic gene expression in mice. We observed that the number of significantly changed genes and the fold-induction of genes increased with increasing fatty acid chain length and degree of unsaturation. Importantly, almost every single gene regulated by dietary unsaturated fatty acids remained unaltered in mice lacking PPARalpha. In addition, the majority of genes regulated by unsaturated fatty acids, especially docosahexaenoic acid, were also regulated by the specific PPARalpha agonist WY14643. Excellent agreement was found between the effects of unsaturated fatty acids on mouse liver versus cultured rat hepatoma cells. Interestingly, using Nuclear Receptor PamChip(R) Arrays, fatty acid- and WY14643-induced interactions between PPARalpha and coregulators were found to be highly similar, although several PPARalpha-coactivator interactions specific for WY14643 were identified.

Conclusions/significance: We conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARalpha and mimic those of synthetic PPARalpha agonists in terms of regulation of target genes and molecular mechanism. Use of synthetic dietary triglycerides may provide a novel paradigm for nutrigenomics research.

Show MeSH

Related in: MedlinePlus

Similarities between two dietary unsaturated fatty acids and the synthetic PPARα agonist WY14643.(A) Venn diagrams showing the overlap in up- (left panel) and downregulated (right panel) genes after treatment with WY14643, C22:6 and C18:1. Genes were considered statistically significantly regulated if P<0.01. (B) Scatter plots demonstrating similarities in gene regulation between C22:6 and WY14643. Graphs show fold change in gene expression after treatment with WY14643 compared to C22:6 and C18:1. Genes that are upregulated disproportionally strongly by WY14643 (Cd36, Fabp4 (aP2), and Cpt1b), or by C22:6 (Prlr and Txnip) are marked. In constructing the scatter plots, all probesets left after IQR-filtering were used. (C) Overlap in overrepresented Gene Ontology classes between C22:6, C18:1, and WY14643, based on a functional class score (FCS) method. The GO class unique to C22:6 and C18:1 is GO:0016070 (RNA metabolism), whereas the GO classes unique to C18:1 are GO:0007409 (axonogenesis) and GO:0016072 (rRNA metabolism).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2244803&req=5

pone-0001681-g003: Similarities between two dietary unsaturated fatty acids and the synthetic PPARα agonist WY14643.(A) Venn diagrams showing the overlap in up- (left panel) and downregulated (right panel) genes after treatment with WY14643, C22:6 and C18:1. Genes were considered statistically significantly regulated if P<0.01. (B) Scatter plots demonstrating similarities in gene regulation between C22:6 and WY14643. Graphs show fold change in gene expression after treatment with WY14643 compared to C22:6 and C18:1. Genes that are upregulated disproportionally strongly by WY14643 (Cd36, Fabp4 (aP2), and Cpt1b), or by C22:6 (Prlr and Txnip) are marked. In constructing the scatter plots, all probesets left after IQR-filtering were used. (C) Overlap in overrepresented Gene Ontology classes between C22:6, C18:1, and WY14643, based on a functional class score (FCS) method. The GO class unique to C22:6 and C18:1 is GO:0016070 (RNA metabolism), whereas the GO classes unique to C18:1 are GO:0007409 (axonogenesis) and GO:0016072 (rRNA metabolism).

Mentions: To further explore the role of PPARα in regulation of gene expression by dietary unsaturated fatty acids, the overlap in gene regulation between fatty acids and WY14643, which specifically targets PPARα, was studied. Remarkably, C22:6 showed a huge overlap in gene regulation with WY14643 (Figure 3A). Quantitatively, 84% of genes upregulated and 76% of genes downregulated by C22:6 (P<0.01) were also regulated by WY14643 (average 80.5%), suggesting that C22:6 impacts mainly PPARα target genes. Much less overlap was observed between C18:1 and WY14643 (average 32.4%), suggesting that gene regulation by C18:1 may be less dependent on PPARα, or alternatively the existence of PPARα target genes specifically regulated by C18:1 (Figure 3A). An intermediate degree of overlap was observed between WY14643 and the other fatty acids studied (Table S2).


Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics.

Sanderson LM, de Groot PJ, Hooiveld GJ, Koppen A, Kalkhoven E, Müller M, Kersten S - PLoS ONE (2008)

Similarities between two dietary unsaturated fatty acids and the synthetic PPARα agonist WY14643.(A) Venn diagrams showing the overlap in up- (left panel) and downregulated (right panel) genes after treatment with WY14643, C22:6 and C18:1. Genes were considered statistically significantly regulated if P<0.01. (B) Scatter plots demonstrating similarities in gene regulation between C22:6 and WY14643. Graphs show fold change in gene expression after treatment with WY14643 compared to C22:6 and C18:1. Genes that are upregulated disproportionally strongly by WY14643 (Cd36, Fabp4 (aP2), and Cpt1b), or by C22:6 (Prlr and Txnip) are marked. In constructing the scatter plots, all probesets left after IQR-filtering were used. (C) Overlap in overrepresented Gene Ontology classes between C22:6, C18:1, and WY14643, based on a functional class score (FCS) method. The GO class unique to C22:6 and C18:1 is GO:0016070 (RNA metabolism), whereas the GO classes unique to C18:1 are GO:0007409 (axonogenesis) and GO:0016072 (rRNA metabolism).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2244803&req=5

pone-0001681-g003: Similarities between two dietary unsaturated fatty acids and the synthetic PPARα agonist WY14643.(A) Venn diagrams showing the overlap in up- (left panel) and downregulated (right panel) genes after treatment with WY14643, C22:6 and C18:1. Genes were considered statistically significantly regulated if P<0.01. (B) Scatter plots demonstrating similarities in gene regulation between C22:6 and WY14643. Graphs show fold change in gene expression after treatment with WY14643 compared to C22:6 and C18:1. Genes that are upregulated disproportionally strongly by WY14643 (Cd36, Fabp4 (aP2), and Cpt1b), or by C22:6 (Prlr and Txnip) are marked. In constructing the scatter plots, all probesets left after IQR-filtering were used. (C) Overlap in overrepresented Gene Ontology classes between C22:6, C18:1, and WY14643, based on a functional class score (FCS) method. The GO class unique to C22:6 and C18:1 is GO:0016070 (RNA metabolism), whereas the GO classes unique to C18:1 are GO:0007409 (axonogenesis) and GO:0016072 (rRNA metabolism).
Mentions: To further explore the role of PPARα in regulation of gene expression by dietary unsaturated fatty acids, the overlap in gene regulation between fatty acids and WY14643, which specifically targets PPARα, was studied. Remarkably, C22:6 showed a huge overlap in gene regulation with WY14643 (Figure 3A). Quantitatively, 84% of genes upregulated and 76% of genes downregulated by C22:6 (P<0.01) were also regulated by WY14643 (average 80.5%), suggesting that C22:6 impacts mainly PPARα target genes. Much less overlap was observed between C18:1 and WY14643 (average 32.4%), suggesting that gene regulation by C18:1 may be less dependent on PPARα, or alternatively the existence of PPARα target genes specifically regulated by C18:1 (Figure 3A). An intermediate degree of overlap was observed between WY14643 and the other fatty acids studied (Table S2).

Bottom Line: The effect of dietary fats on human health and disease are likely mediated by changes in gene expression.Interestingly, using Nuclear Receptor PamChip(R) Arrays, fatty acid- and WY14643-induced interactions between PPARalpha and coregulators were found to be highly similar, although several PPARalpha-coactivator interactions specific for WY14643 were identified.We conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARalpha and mimic those of synthetic PPARalpha agonists in terms of regulation of target genes and molecular mechanism.

View Article: PubMed Central - PubMed

Affiliation: Nutrigenomics Consortium, Top Institute (TI) Food and Nutrition, Wageningen, The Netherlands.

ABSTRACT

Background: The effect of dietary fats on human health and disease are likely mediated by changes in gene expression. Several transcription factors have been shown to respond to fatty acids, including SREBP-1c, NF-kappaB, RXRs, LXRs, FXR, HNF4alpha, and PPARs. However, it is unclear to what extent these transcription factors play a role in gene regulation by dietary fatty acids in vivo.

Methodology/principal findings: Here, we take advantage of a unique experimental design using synthetic triglycerides composed of one single fatty acid in combination with gene expression profiling to examine the effects of various individual dietary fatty acids on hepatic gene expression in mice. We observed that the number of significantly changed genes and the fold-induction of genes increased with increasing fatty acid chain length and degree of unsaturation. Importantly, almost every single gene regulated by dietary unsaturated fatty acids remained unaltered in mice lacking PPARalpha. In addition, the majority of genes regulated by unsaturated fatty acids, especially docosahexaenoic acid, were also regulated by the specific PPARalpha agonist WY14643. Excellent agreement was found between the effects of unsaturated fatty acids on mouse liver versus cultured rat hepatoma cells. Interestingly, using Nuclear Receptor PamChip(R) Arrays, fatty acid- and WY14643-induced interactions between PPARalpha and coregulators were found to be highly similar, although several PPARalpha-coactivator interactions specific for WY14643 were identified.

Conclusions/significance: We conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARalpha and mimic those of synthetic PPARalpha agonists in terms of regulation of target genes and molecular mechanism. Use of synthetic dietary triglycerides may provide a novel paradigm for nutrigenomics research.

Show MeSH
Related in: MedlinePlus