Hepatic PPARalpha is critical in the metabolic adaptation to sepsis
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ABSTRACT:
PROVIDER: PRJNA498629 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Sepsis induces a metabolic shift from glucose to fatty acid utilization that is key to survival for the organism. Here we used microarray analysis to characterize hepatic gene expression in conditions mimicking sepsis.
2019-02-01 | GSE121847 | GEO
Project description:Role of PPARalpha in the effects of DEHP on the hepatic expression of a selection of mouse genes related to nuclear receptor signaling. Di-(2-ethylhexyl)-phthalate (DEHP), a widely used plasticizer, is detected in consumer’s body fluids. Contamination occurs through environmental and food chain sources. In mouse liver, DEHP activates the peroxisome proliferator-activated receptor alpha (PPARalpha) and regulates the expression of its target genes. Several in vitro investigations support the simultaneous recruitment of additional nuclear receptor pathways. We investigated, in vivo, the hepatic impact of low doses of DEHP on PPARalpha activation, and the putative activation of additional signalling pathways. Wild-type and PPARalpha-deficient mice were exposed to different doses of DEHP. Gene expression profiling delineated the role of PPARalpha and revealed a PPARalpha-independent regulation of several prototypic Constitutive Androstane Receptor (CAR) target genes. This finding demonstrates that CAR also represents a transcriptional regulator sensitive to phthalates. CAR-mediated effects of DEHP provide a new rationale for most endpoints of phthalates toxicity described previously, including endocrine disruption, hepatocarcinogenesis and the metabolic syndrome. Keywords: Treatment effect
2009-02-26 | GSE14920 | GEO
Project description:This SuperSeries is composed of the following subset Series:; GSE8290: Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling - 1; GSE8291: Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling - 2; GSE8292: Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling - 3; GSE8295: Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling - 4; GSE8302: Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling - 5; PPARalpha is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARalpha in hepatic lipid metabolism, many PPARalpha-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARalpha-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARalpha target genes, livers from several animal studies in which PPARalpha was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARalpha-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARalpha-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein beta polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (HSL, 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. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, 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 PPARalpha 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 PPARalpha. Our study illustrates the power of transcriptional profiling to uncover novel PPARalpha-regulated genes and pathways in liver. Experiment Overall Design: Refer to individual Series
2008-06-16 | E-GEOD-8316 | biostudies-arrayexpress
Project description:In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis and organ damage and prevents an adequate response towards IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all possible levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in disease tolerance to sepsis. In conclusion, hepatic HNF4α fails in sepsis, causing PPARα downregulation and metabolic problems and a disturbed IL6-mediated acute phase response. The data open new insights and therapeutic options in sepsis.
2023-10-31 | GSE244821 | GEO
Project description:In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis and organ damage and prevents an adequate response towards IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all possible levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in disease tolerance to sepsis. In conclusion, hepatic HNF4α fails in sepsis, causing PPARα downregulation and metabolic problems and a disturbed IL6-mediated acute phase response. The data open new insights and therapeutic options in sepsis.
2023-10-31 | GSE245682 | GEO
Project description:Role of PPARalpha in the effects of DEHP on the hepatic expression of a selection of mouse genes related to nuclear receptor signaling. Di-(2-ethylhexyl)-phthalate (DEHP), a widely used plasticizer, is detected in consumerâs body fluids. Contamination occurs through environmental and food chain sources. In mouse liver, DEHP activates the peroxisome proliferator-activated receptor alpha (PPARalpha) and regulates the expression of its target genes. Several in vitro investigations support the simultaneous recruitment of additional nuclear receptor pathways. We investigated, in vivo, the hepatic impact of low doses of DEHP on PPARalpha activation, and the putative activation of additional signalling pathways. Wild-type and PPARalpha-deficient mice were exposed to different doses of DEHP. Gene expression profiling delineated the role of PPARalpha and revealed a PPARalpha-independent regulation of several prototypic Constitutive Androstane Receptor (CAR) target genes. This finding demonstrates that CAR also represents a transcriptional regulator sensitive to phthalates. CAR-mediated effects of DEHP provide a new rationale for most endpoints of phthalates toxicity described previously, including endocrine disruption, hepatocarcinogenesis and the metabolic syndrome. Keywords: Treatment effect One-color macroarrays, 6 experimental conditions: Wild type (WT) and PPARalpha-deficient mice (PPAR) were treated with vehicle (Ctrl) or with di-(2-ethylhexyl)-phthalate (DEHP) at 20 mg/kg/day (D20) or 200 mg/kg/day (D200) for 21 days, Biological replicates: 10 for each group, One replicate per array
2010-05-22 | E-GEOD-14920 | biostudies-arrayexpress
Project description:Hepatic PPARα dysfunction in porcine sepsis
| PRJNA904738 | ENA
Project description:Sepsis is a maladaptive host response towards an infection leading to tissue damage, organ failure, and ultimately death. In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is hindered by hepatic disappearance of the key transcription factor PPARα. Since PPARα acts as a central player in intracellular catabolism of fatty acids (FAs), sepsis results in excess free FAs, which cause lipotoxicity. The mechanism upstream of the PPARα downregulation in sepsis is unknown. A potential mechanism resides in HNF4α, which regulates liver lipid metabolism directly by activating Ppara gene expression and indirectly by interacting with PPARα itself. A proper functioning of HNF4α is essential for maintaining liver identity. We here show that sepsis causes a progressive HNF4α loss-of-function in the liver, which impacts expression of several nuclear receptors, among which PPARα, and is characterized by a reduced HNF4α DNA binding. Specific HNF4α depletion in the liver dramatically worsens sepsis lethality, associated with increased steatosis and hepatocyte damage. HNF4α dysfunction also prevents an adequate response towards IL6, controlled by CEBPβ and STAT3, which is critical for a proper liver regeneration and survival. In addition, the HNF4α agonist NCT partially protects against sepsis by limiting hepatic steatosis and liver dysfunction. In conclusion, hepatic HNF4α fails in sepsis, causing PPARα downregulation and consequent metabolic problems on the one hand, and a disturbed IL6-mediated acute phase response and regeneration on the other hand. The data open new insights and therapeutic options in sepsis
2024-03-12 | GSE260577 | GEO
Project description:Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease, however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARa is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARa in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARa levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARa agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARa function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point towards new therapeutic leads in sepsis.
2019-11-23 | GSE139484 | GEO
Project description:A functional interaction between peroxisome proliferator-activated receptor alpha (PPARalpha) and components of the circadian clock has been suggested; however, it remains to be clarified whether those transcriptional factors interact with each other to regulate the expression of their target genes. In this study, we used a ligand of PPARalpha, bezafibrate, to search the PPARalpha-regulated genes that express in a CLOCK-dependent circadian manner. Microarrays analyses using hepatic RNA isolated from bezafibrate treated-wild type, Clock mutant (Clk/Clk), and PPARalpha-null mice revealed that 136 genes are transcriptionally regulated by PPARalpha in a CLOCK-dependent manner.
2010-06-15 | GSE20513 | GEO