Prenatal PPARa-dependent gene expression in fetal mouse liver just before birth (E19.5)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Gianpaolo Rando
PROVIDER: E-GEOD-39669 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Inborn errors of lipid metabolism illustrate the importance of proper milk fat oxidation in newborn mammals. In the liver, a remarkable lipid catabolic competence is present at birth; however, it is unclear how this critical trait is acquired and regulated. In this work, we found that the genes required for milk lipid catabolism are already transcribed before birth in the term fetus (E19.5) and controlled by the peroxisome-proliferator activated receptor alpha (PPARα) in mouse liver. The developmental activity of PPARα strongly regulates fatty acid oxidation genes. Two days after birth (P2), during milk suckling, PPARα-null mice develop a congenital steatosis and milk protein oxidation is de-repressed to fuel an alternative energy pathway that maintains glucose homeostasis and postnatal growth. Our results demonstrate for the first time, the developmental role of PPARα in regulating the metabolic ability to use maternal milk as fuel in the early days of life. Expression profile difference between PPARalpha wild-type (3 males and 3 females) and knock-out (3 males and 3 females) mouse liver in suckling mice. Two days after birth, pups were killed and their liver promptly removed and frozen in liquid nitrogen.
2016-06-01 | E-GEOD-39670 | biostudies-arrayexpress
Project description:Inborn errors of lipid metabolism illustrate the importance of proper milk fat oxidation in newborn mammals. In the liver, a remarkable lipid catabolic competence is present at birth; however, it is unclear how this critical trait is acquired and regulated. In this work, we found that the genes required for milk lipid catabolism are already transcribed before birth in the term fetus (E19.5) and controlled by the peroxisome-proliferator activated receptor alpha (PPARα) in mouse liver. The developmental activity of PPARα strongly regulates fatty acid oxidation genes. Two days after birth (P2), during milk suckling, PPARα-null mice develop a congenital steatosis and milk protein oxidation is de-repressed to fuel an alternative energy pathway that maintains glucose homeostasis and postnatal growth. Our results demonstrate for the first time, the developmental role of PPARα in regulating the metabolic ability to use maternal milk as fuel in the early days of life.
2016-06-01 | GSE39669 | GEO
Project description:Inborn errors of lipid metabolism illustrate the importance of proper milk fat oxidation in newborn mammals. In the liver, a remarkable lipid catabolic competence is present at birth; however, it is unclear how this critical trait is acquired and regulated. In this work, we found that the genes required for milk lipid catabolism are already transcribed before birth in the term fetus (E19.5) and controlled by the peroxisome-proliferator activated receptor alpha (PPARα) in mouse liver. The developmental activity of PPARα strongly regulates fatty acid oxidation genes. Two days after birth (P2), during milk suckling, PPARα-null mice develop a congenital steatosis and milk protein oxidation is de-repressed to fuel an alternative energy pathway that maintains glucose homeostasis and postnatal growth. Our results demonstrate for the first time, the developmental role of PPARα in regulating the metabolic ability to use maternal milk as fuel in the early days of life.
2016-06-01 | GSE39670 | GEO
Project description:Background: We previously reported that intake of a water-soluble extract of Pacific Krill (WEPAK) by mice decreases triglyceride accumulation in liver and suppresses weight gain induced by a high-fat diet. However, the mechanisms mediating these phenomena were not investigated or revealed in our previous study. Methods and Findings: Here, we investigated the effect of WEPAK in mouse liver using transcriptome analysis and discovered that WEPAK induced the expression of genes categorized into the gene ontology (GO) term lipid metabolic process. Furthermore, two regulators of fatty acid β-oxidation, AMPK and PPARδ, were induced in the liver and muscle of mice that had taken in WEPAK. Conclusions: These results indicate that WEPAK increased the expression of genes related to fatty acid β-oxidation via activation of AMPK and PPARδ. WEPAK may have the effect of improving lipid metabolism and, therefore, may be beneficial in the prevention of obesity. Examination of 4 different feeding condtion (4mice/group)
2013-04-22 | E-GEOD-37379 | biostudies-arrayexpress
Project description:Background: Studies in mice have shown that PPARα is an important regulator of lipid metabolism in liver and a key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPARα in human liver. Here we set out to study the function of PPARα in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPARα agonist Wy14643. Results: Quantitative PCR indicated that PPARα is well expressed in human liver and human liver slices and that the classical PPARα targets PLIN2, VLDLR, ANGPTL4, CPT1A and PDK4 are robustly induced by PPARα activation. Transcriptomics analysis indicated that 617 genes were upregulated and 665 genes were downregulated by PPARα activation (q value<0.05). Many genes induced by PPARα activation were involved in lipid metabolism (ACSL5, AGPAT9, FADS1, SLC27A4), xenobiotic metabolism (POR, ABCC2, CYP3A5) or the unfolded protein response, whereas most of the downregulated genes were involved in immune-related pathways. Among the most highly repressed genes upon PPARα activation were several chemokines (e.g. CXCL9-11, CCL8, CX3CL1, CXCL6), interferon γ-induced genes (e.g. IFITM1, IFIT1, IFIT2, IFIT3) and numerous other immune-related genes (e.g. TLR3, NOS2, and LCN2). Comparative analysis of gene regulation by Wy14643 between human liver slices and primary human hepatocytes showed that down-regulation of gene expression by PPARα is much better captured by liver slices as compared to primary hepatocytes. In particular, PPARα activation markedly suppressed immunity/inflammation-related genes in human liver slices but not in primary hepatocytes. Finally, several putative new target genes of PPARα were identified that were commonly induced by PPARα activation in the two human liver model systems, including TSKU, RHOF, CA12 and VSIG10L. Conclusion: Our manuscript demonstrates the suitability and superiority of human liver slices over primary hepatocytes for studying the functional role of PPARα in human liver. Our data underscore the major role of PPARα in regulation of hepatic lipid and xenobiotic metabolism in human liver and reveal a marked immuno-suppressive/anti-inflammatory effect of PPARα in human liver slices that may be therapeutically relevant for non-alcoholic fatty liver disease. Precision-cut liver slices, prepared from liver biopsies obtained from obese subjects undergoing bariatric surgery, were incubated with the peroxisome proliferator-activated receptor alpha (PPARα) agonist Wy14643 or vehicle for 24hrs, after which gene expression was profiled by array.
2015-11-23 | E-GEOD-71731 | biostudies-arrayexpress
Project description:Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARα target gene in liver, but its function in hepatic lipid metabolism is unknown. We investigated the regulation of vanin-1, and total vanin activity, by PPARα in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity. Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARα activity. In addition, activation of mouse PPARα regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARα, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARα agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation. We show that hepatic vanin-1 is under extremely sensitive regulation by PPARα and that plasma vanin activity could serve as a readout of changes in PPARα activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting. Livers of wild type and vanin-1 knockout mice that were fed or fasted for 24h were subjected to gene expression analysis
2014-04-24 | E-GEOD-51712 | biostudies-arrayexpress
Project description:The role of peroxisome proliferator-activated receptor M-NM-4 (PPARM-NM-4) activation on global gene expression and mitochondrial fuel utilization were investigated in human myotubes. Only 21 genes were up-regulated and 3 genes were down-regulated after activation by the PPARM-NM-4 agonist GW501516. Pathway analysis showed up-regulated mitochondrial fatty acid oxidation, TCA cycle and cholesterol biosynthesis. GW501516 increased oleic acid oxidation and mitochondrial oxidative capacity by 2-fold. Glucose uptake and oxidation were reduced, but total substrate oxidation was not affected, indicating a fuel switch from glucose to fatty acid. Cholesterol biosynthesis was increased, but lipid biosynthesis and mitochondrial content were not affected. This study confirmed that the principal effect of PPARM-NM-4 activation was to increase mitochondrial fatty acid oxidative capacity. Our results further suggest that PPARM-NM-4 activation reduced glucose utilization through a switch in mitochondrial substrate preference by up-regulating pyruvate dehydrogenase kinase isozyme 4 and genes involved in lipid metabolism and fatty acid oxidation. Keywords: Expression profiling by array Human myotubes from four donors were exposed to a PPARM-NM-4 agonist or control for 96 h after which gene expression was profiled.
2014-05-23 | E-GEOD-40789 | biostudies-arrayexpress
Project description:PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein β polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver. Experiment Overall Design: 3-5 months old male pure bred wild-type (129S1/SvImJ) and PPARα-null (129S4/SvJae) mice were used. Experiment Overall Design: Wild-type and PPARα-null mice were treated with the synthetic PPARα ligand Wy14643 (0.1% w/w) mixed in the food, or normal food (control) for 5 days (n=4 per group). Liver total RNA from biological replicates was hybridized onto Affymetrix mouse genome 430 2.0 GeneChip arrays. Experiment Overall Design: Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.
2008-06-16 | E-GEOD-8295 | biostudies-arrayexpress
Project description:PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein β polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver. Experiment Overall Design: 3-5 months old male pure bred wild-type (129S1/SvImJ) and PPARα-null (129S4/SvJae) mice were used. Experiment Overall Design: Fed mice were killed at the end of the dark cycle (wild-type and PPARα-null mice; n=5 per group), mice were fasted for 24h before sacrifice (wild-type and PPARα-null mice; n=5 per group). Liver total RNA of pooled samples (within groups) was hybridized onto Affymetrix MOE430A GeneChip arrays. Experiment Overall Design: Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.
2008-06-16 | E-GEOD-8290 | biostudies-arrayexpress
Project description:PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein β polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Since Pnpla2, Lipe, and Mgll contribute to hepatic triglyceride hydrolysis, gene regulation was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver. Experiment Overall Design: 3-5 months old male pure bred wild-type (129S1/SvImJ) and PPARα-null (129S4/SvJae) mice were used. Experiment Overall Design: Wild-type and PPARα-null mice were treated with the synthetic PPARα ligand WY14643 (0.1% w/w) mixed in the food, or normal food (control) for 5 days (n=5 per group). Liver total RNA of pooled samples (within groups) was hybridized onto Affymetrix MOE430A GeneChip arrays. Experiment Overall Design: Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.
2008-06-16 | E-GEOD-8291 | biostudies-arrayexpress