Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Detailed transcriptomics analysis of the effect of dietary fatty acids 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 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.

ORGANISM(S): Mus musculus

SUBMITTER: Guido Hooiveld

PROVIDER: E-GEOD-30495 | 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 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.

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:Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to explore the possible mechanisms involved. To that end, C57Bl/6 mice rendered obese and steatotic by chronic high-fat feeding were treated for 1 week with clodronate liposomes, which cause depletion of Kupffer cells. Loss of expression of marker genes Cd68, F4/80, and Clec4f, and loss of Cd68 immunostaining verified almost complete removal of Kupffer cells from the liver. Also, expression of complement components C1, the chemokine (C-C motif) ligand 6 (Ccl6), and cytokines interleukin-15 (IL-15) and IL-1beta were markedly reduced. Importantly, Kupffer cell depletion significantly decreased liver triglyceride and glucosylceramide levels concurrent with increased expression of genes involved in fatty acid oxidation including peroxisome proliferator-activated receptor alpha (PPARalpha), carnitine palmitoyltransferase 1A (Cpt1alpha), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1beta decreased expression of PPARalpha and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1beta suppressed human and mouse PPARalpha promoter activity. Suppression of PPARalpha promoter activity was recapitulated by overexpression of nuclear factor kappaB (NF-kappaB) subunit p50 and p65, and was abolished upon deletion of putative NF-kappaB binding sites. Finally, IL-1beta and NF-kappaB interfered with the ability of PPARalpha to activate gene transcription. CONCLUSION: Our data point toward important cross-talk between Kupffer cells and hepatocytes in the regulation of hepatic triglyceride storage. The effect of Kupffer cells on liver triglycerides are at least partially mediated by IL-1beta, which suppresses PPARalpha expression and activity. Expression profiling of livers from mice fed control, low-fat diet diet or high-fat diet for 20weeks with or without knockdown of Kupffer cells.

Dataset Information

Detailed transcriptomics analysis of the effect of dietary fatty acids 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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