Unknown,Transcriptomics,Genomics,Proteomics

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Detailed transcriptomics analysis of the effect of the PPARalpha agonist Wy14,643 on gene regulation in the murine heart

ABSTRACT: Fatty acids comprise the primary energy source for the heart and are mainly taken up via hydrolysis of circulating triglyceride-rich lipoproteins. While most of the fatty acids entering the cardiomyocyte are oxidized, a small portion is involved in altering gene transcription to modulate cardiometabolic functions. So far, no in vivo model has been developed enabling study of the transcriptional effects of specific fatty acids in the intact heart. In the present study, mice were given a single oral dose of synthetic triglycerides composed of one single fatty acid. Hearts were collected 6h thereafter and used for whole genome gene expression profiling. Experiments were conducted in wild-type and PPARM-NM-1M-bM-^HM-^R/M-bM-^HM-^R mice to allow exploration of the specific contribution of PPARM-NM-1. It was found that: 1) linolenic acid (C18:3) had the most pronounced effect on cardiac gene expression. 2) The largest similarity in gene regulation was observed between linoleic acid (C18:2) and C18:3. Large similarity was also observed between the synthetic PPARM-NM-1 agonist Wy14,643 and docosahexaenoic acid (C22:6). 3) Many genes were regulated by one particular treatment only. Genes regulated by one particular treatment showed large functional divergence. 4) The majority of genes responding to fatty acid treatment were regulated in a PPARM-NM-1-dependent manner, emphasizing the importance of PPARM-NM-1 in mediating transcriptional regulation by fatty acids in the heart. 5) Several genes were robustly regulated by all or many of the fatty acids studied, mostly representing well-described targets of PPARs (e.g. Acot1, Angptl4, Ucp3). 6) Deletion and activation of PPARM-NM-1 had a major effect on expression of numerous genes involved in metabolism and immunity. Our analysis demonstrates the marked impact of dietary fatty acids on gene regulation in the heart via PPARM-NM-1. To study the long term transcriptional effects of PPARM-NM-1 activation, wild type and PPARM-NM-1M-bM-^HM-^R/M-bM-^HM-^R mice were fed a chow diet (RMH-B diet Arie Block, Woerden, the Netherlands) containing 0.1% (w/w) of the specific PPARM-NM-1 agonist Wy14,643. After 5days hearts were collected and used for whole genome gene expression profiling.

ORGANISM(S): Mus musculus

SUBMITTER: Guido Hooiveld

PROVIDER: E-GEOD-30553 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Detailed transcriptomics analysis of the effect of dietary fatty acids on gene expression in the heart.

Georgiadi Anastasia A Boekschoten Mark V MV Müller Michael M Kersten Sander S

Physiological genomics 20120124 6

Fatty acids comprise the primary energy source for the heart and are mainly taken up via hydrolysis of circulating triglyceride-rich lipoproteins. While most of the fatty acids entering the cardiomyocyte are oxidized, a small portion is involved in altering gene transcription to modulate cardiometabolic functions. So far, no in vivo model has been developed enabling study of the transcriptional effects of specific fatty acids in the intact heart. In the present study, mice were given a single or ...[more]

PMID: 22274564

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Project description:Fatty acids comprise the primary energy source for the heart and are mainly taken up via hydrolysis of circulating triglyceride-rich lipoproteins. While most of the fatty acids entering the cardiomyocyte are oxidized, a small portion is involved in altering gene transcription to modulate cardiometabolic functions. So far, no in vivo model has been developed enabling study of the transcriptional effects of specific fatty acids in the intact heart. In the present study, mice were given a single oral dose of synthetic triglycerides composed of one single fatty acid. Hearts were collected 6h thereafter and used for whole genome gene expression profiling. Experiments were conducted in wild-type and PPARalpha-/- mice to allow exploration of the specific contribution of PPARalpha. It was found that: 1) linolenic acid (C18:3) had the most pronounced effect on cardiac gene expression. 2) The largest similarity in gene regulation was observed between linoleic acid (C18:2) and C18:3. Large similarity was also observed between the synthetic PPARalpha agonist Wy14643 and docosahexaenoic acid (C22:6). 3) Many genes were regulated by one particular treatment only. Genes regulated by one particular treatment showed large functional divergence. 4) The majority of genes responding to fatty acid treatment were regulated in a PPARalpha-dependent manner, emphasizing the importance of PPARalpha in mediating transcriptional regulation by fatty acids in the heart. 5) Several genes were robustly regulated by all or many of the fatty acids studied, mostly representing well-described targets of PPARs (e.g. Acot1, Angptl4, Ucp3). 6) Deletion and activation of PPARalpha had a major effect on expression of numerous genes involved in metabolism and immunity. Our analysis demonstrates the marked impact of dietary fatty acids on gene regulation in the heart via PPARalpha. To study the transcriptional effects of specific fatty acids in the intact heart, wild type and PPARalpha-/- mice were given a single oral dose of 4 synthetic triglycerides composed of one single fatty acid, as well as of the synthetic PPARalpha agonist Wy14,643. Hearts were collected 6h after gavag and used for whole genome gene expression profiling.

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.

Project description:The transcription factor Peroxisome Proliferator-Activated Receptor M-NM-1 (PPARM-NM-1) is an important regulator of hepatic lipid metabolism. While PPARM-NM-1 is known to activate transcription of numerous genes, no comprehensive picture of PPARM-NM-1 binding to endogenous genes has yet been reported. To fill this gap, we performed ChIP-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPARM-NM-1 agonist GW7647. We found that GW7647 increased PPARM-NM-1 binding to 4220 binding regions. GW7647-induced binding regions showed a bias around the transcription start site and most contained a predicted PPAR binding motif. Several genes known to be regulated by PPARM-NM-1, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARM-NM-1 binding to their promoter. A GW7647-induced PPARM-NM-1-binding region was also assigned to SREBP-targets HMGCS1, HMGCR, FDFT1, SC4MOL, and LPIN1, expression of which was induced by GW7647, suggesting cross-talk between PPARM-NM-1 and SREBP signaling. Our data furthermore demonstrate interaction between PPARM-NM-1 and STAT transcription factors in PPARM-NM-1-mediated transcriptional repression, and suggest interaction between PPARM-NM-1 and TBP and C/EBPM-NM-1 in PPARM-NM-1-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARM-NM-1 in human liver and highlight the importance of cross-talk with other transcription factors. HepG2 cells were grown in phenol red-free DulbeccoM-bM-^@M-^Ys modified medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 0.1 mg/ml streptomycin and 100 U/ml penicillin. Cells were split the day before experiments. Cells were kept at 37 M-BM-0C and 5% CO2. The following day, cells were treated with either 100 nM of the PPARM-NM-1 agonist GW7647 or control vehicle (DMSO). Cells used for gene expression analysis were harvested after 6 h or 24 h of GW7647 treatment. This submission represents the gene expression component of the study.

Dataset Information

Detailed transcriptomics analysis of the effect of the PPARalpha agonist Wy14,643 on gene regulation in the murine heart

Publications

Detailed transcriptomics analysis of the effect of dietary fatty acids on gene expression in the heart.

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