Abstract
BackgroundThe 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-κB, RXRs, LXRs, FXR, HNF4α, 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 FindingsHere, 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 PPARα. In addition, the majority of genes regulated by unsaturated fatty acids, especially docosahexaenoic acid, were also regulated by the specific PPARα 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® Arrays, fatty acid- and WY14643-induced interactions between PPARα and coregulators were found to be highly similar, although several PPARα-coactivator interactions specific for WY14643 were identified.Conclusions/SignificanceWe conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARα and mimic those of synthetic PPARα agonists in terms of regulation of target genes and molecular mechanism. Use of synthetic dietary triglycerides may provide a novel paradigm for nutrigenomics research.
Highlights
Dietary fatty acids have multiple functions in the human body
We observed that 6 hours after oral dosing plasma TG levels had almost returned to baseline (Figure S1B), and were similar in WT and PPARa 2/2 mice, suggesting no major differences in plasma TG kinetics between the various fatty acids and between WT and PPARa 2/2
While as expected liver TG levels were higher in the PPARa 2/2 mice compared to WT mice, in the WT mice liver TG levels were similar between the various fatty acids (Figure S1D)
Summary
Dietary fatty acids have multiple functions in the human body. They are an important energy source, form an essential part of the phospholipid bilayer of membranes, and function as precursors to several signaling molecules, such as the eicosanoids. Adopted orphan receptors mainly function as lipid sensors by altering the rate of transcription of specific genes in response to changes in lipid concentration [6]. These lipids include oxysterols, bile acids, and fat soluble vitamins. Many adopted orphan receptors have been shown to bind fatty acids and alter transcription in response to changes in fatty acid concentration and/or composition, including RXR, Peroxisome-Proliferator Activated Receptors (PPARa, b/d and c), Hepatic Nuclear Factor 4a (HNF-4a), Liver X Receptor (LXR) a and b, and Farnesoid X Receptor [7,8]. We conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost exclusively mediated by PPARa and mimic those of synthetic PPARa agonists in terms of target genes regulation and molecular mechanism
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
