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


RESULTS
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
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.
Sanderson
Linda M
LM
Nutrigenomics Consortium, Top Institute (TI) Food and Nutrition, Wageningen, The Netherlands.
de Groot
Philip J
PJ
Hooiveld
Guido J E J
GJ
Koppen
Arjen
A
Kalkhoven
Eric
E
Müller
Michael
M
Kersten
Sander
S
D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000138:chemical synthesis / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D047493:PPAR alpha / Q000502:physiology*; D051381:Rats; D013329:Structure-Activity Relationship; D014157:Transcription Factors; D014280:Triglycerides / Q000138:chemical synthesis / Q000494:pharmacology*
D004041:Dietary Fats; D047493:PPAR alpha; D014157:Transcription Factors; D014280:Triglycerides