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Impact of dietary fatty acids on gene expression of liver-specific knockout of cytochrome P450 reductase

ABSTRACT: In the present study, we explored the hypothesis that the fatty liver phenotype and associated gene expression changes associated with the specific deletion of the POR gene in adult mouse liver could be abrogated by supplementation of the mouse diet with the very long chain highly unsaturated fatty acids, arachidonic acid (C20:4ω6), eicosapentaenoic acid (C20:5ω3) and docosahexaenoic acid (C22:6ω3). We expected the fatty liver phenotype would not be reduced by the polyunsaturated fatty acids linoleic (C18:2ω6) or linolenic acid (C18:3ω3), since these accumulated in the fatty livers of LivPORKO animals. This proved to be the case. However, we also made two surprising observations. First, control animals fed a diet enriched in PUFA had fatty livers and gene expression profiles similar to animals fed a lard diet, which was deficient in both PUFA and HUFA. Second, while a diet enriched in HUFA did result in reduced steatosis in livers of the LivPOKO animals, fat accumulation was still elevated relative to controls. Array analyses indicated most differences in gene expression were related to fatty acid metabolism and could explain differences in fat accumulation in LivPORKO livers with dietary treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE20944 | GEO | 2010/10/09

SECONDARY ACCESSION(S): PRJNA124425

REPOSITORIES: GEO

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Project description:The optimal ratio of omega-6 to omega-3 polyunsaturated fatty acids (PUFAs) is important for keeping homeostasis of biological processes and metabolism, yet the underlying biological mechanism is poorly understood. The objective of this study was to identify changes in the pig liver transcriptome induced by a diet enriched with omega-6 and omega-3 fatty acids, and to characterize the biological mechanisms related to PUFA metabolism. Polish Landrace pigs (n =12) were fed diet enriched with linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3 family) or standard diet as a control. The fatty acids profiling was assayed in order to verify how feeding influenced the fatty acids content in liver, and subsequently next-generation sequencing (NGS) was used to identify differentially expressed genes (DEG) between transcriptomes between dietary groups. The biological mechanisms and pathway interaction networks were identified by analysis in DAVID and Cytoscape tools. Fatty acids profile analysis indicated a higher contribution of PUFAs in liver for LA and ALA-enriched diet group, particularly for the omega-3 fatty acids family, but not omega-6. Next-generation sequencing identified 3,565 DEG, 1,484 of which were induced and 2,081 were suppressed by PUFA supplemenation. Low ratio of omega-6/-3 fatty acids resulted in modulation of fatty acids metabolism pathways and over-representation of genes involved in membrane composition, signal transduction and immune response pathways. In conclusion, a diet enriched with omega-6 and omega-3 fatty acids altered the transcriptomic profile of the pig liver and affected a set of genes involved in metabolic pathways important to animal health status. Hepatic mRNA profiles of Polish Landrace pig breed fed two different diets, were generated by deep sequencing, using Illumina MiSeq. Experimental diet was enriched with polyunsaturated fatty acids (omega-6 and omega-3), while standard diet remain as a cotrol. 2 pooled samples each containing RNA extracts from 6 individuals livers were analyzed.

Project description:Dietary fatty acids have myriads of effects on human health and disease. Many of these effects are likely achieved by altering expression of genes. Several transcription factors have been shown to be responsive to fatty acids, including SREBP-1c, NF-kB, RXRs, LXRs, FXR, HNF4Î±, and PPARs. However, the relative importance of these transcription factors in regulation of gene expression by dietary fatty acids remains unclear. 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 acute effects of individual dietary fatty acids on hepatic gene expression in mice. The dietary interventions were performed in parallel in wild-type and PPARÎ±-/- mice, enabling the determination of the specific contribution of PPARÎ±. Depending on chain length and degree of saturation, dietary fatty acids caused a statistically significant change in expression of over 400 genes. Surprisingly, the far majority of genes regulated by dietary fatty acids in wild-type mice were unaltered in mice lacking PPARÎ±, indicating PPARÎ±-dependent regulation. We conclude that the effects of dietary fatty acids on hepatic gene expression are almost entirely mediated by PPARÎ±, indicating that PPARÎ± dominates fatty acid-dependent gene regulation in liver. Experiment Overall Design: 2-6 months old male pure bred wild-type (129S1/SvImJ) and PPARÎ± -/- (129S4/SvJae) mice were used. Experiment Overall Design: Wild-type and PPARÎ± -/- mice fasted for 4 hours received a single dose of 400 Âµl synthetic triglyceride (tridecanoin â C10:0, triolein â C18:1, trilinolein â C18:2, trilinolenin â C18:3, trieicosapentaenoin â C20:5 or tridocosahexaenoin â C22:6), the synthetic PPARÎ± agonists WY14643 or fenofibrate (400 Î¼l of 10 mg/ml in 0.5% carboxymethyl cellulose, CMC) or control (400 Î¼l of 0.5% CMC). 6 hours after gavage, mice were killed and livers extracted. Experiment Overall Design: (Please note: Experiments with C10:0, C18:2 and C18:3 were carried out a few months later than the rest of the treatments. Therefore there is a second set of control arrays â named control2 â which belong to these three treatment groups.) Experiment Overall Design: Liver total RNA from biological replicates was hybridized onto Affymetrix mouse genome 430 2.0 GeneChip arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

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Impact of dietary fatty acids on gene expression of liver-specific knockout of cytochrome P450 reductase

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