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Acute genome-wide effects of rosiglitazone on PPAR? transcriptional networks in adipocytes.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is a master regulator of adipocyte differentiation, and genome-wide studies indicate that it is involved in the induction of most adipocyte genes. Here we report, for the first time, the acute effects of the synthetic PPAR? agonist rosiglitazone on the transcriptional network of PPAR? in adipocytes. Treatment with rosiglitazone for 1 hour leads to acute transcriptional activation as well as repression of a number of genes as determined by genome-wide RNA polymerase II occupancy. Unlike what has been shown for many other nuclear receptors, agonist treatment does not lead to major changes in the occurrence of PPAR? binding sites. However, rosiglitazone promotes PPAR? occupancy at many preexisting sites, and this is paralleled by increased occupancy of the mediator subunit MED1. The increase in PPAR? and MED1 binding is correlated with an increase in transcription of nearby genes, indicating that rosiglitazone, in addition to activating the receptor, also promotes its association with DNA, and that this is causally linked to recruitment of mediator and activation of genes. Notably, both rosiglitazone-activated and -repressed genes are induced during adipogenesis. However, rosiglitazone-activated genes are markedly more associated with PPAR? than repressed genes and are highly dependent on PPAR? for expression in adipocytes. By contrast, repressed genes are associated with the other key adipocyte transcription factor CCAAT-enhancer binding protein? (C/EBP?), and their expression is more dependent on C/EBP?. This suggests that the relative occupancies of PPAR? and C/EBP? are critical for whether genes will be induced or repressed by PPAR? agonist.

SUBMITTER: Haakonsson AK

PROVIDER: S-EPMC5415231 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Acute genome-wide effects of rosiglitazone on PPARγ transcriptional networks in adipocytes.

Haakonsson Anders Kristian AK Stahl Madsen Maria M Nielsen Ronni R Sandelin Albin A Mandrup Susanne S

Molecular endocrinology (Baltimore, Md.) 20130724 9

Peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation, and genome-wide studies indicate that it is involved in the induction of most adipocyte genes. Here we report, for the first time, the acute effects of the synthetic PPARγ agonist rosiglitazone on the transcriptional network of PPARγ in adipocytes. Treatment with rosiglitazone for 1 hour leads to acute transcriptional activation as well as repression of a number of genes as determined by geno ...[more]

PMID: 23885096

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Project description:BackgroundPulmonary edema is one of the pathological characteristics of acute respiratory distress syndrome (ARDS). The epithelial sodium channel (ENaC) is thought to be the rate-limiting factor for alveolar fluid clearance (AFC) during pulmonary edema. The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone was shown to stimulate ENaC-mediated salt absorption in the kidney. However, its role in the lung remains unclear. Here, we investigated the role of the PPARγ agonist in the lung to find out whether it can regulate AFC during acute lung injury (ALI). We also attempted to elucidate the mechanism for this.MethodsOur ALI model was established through intratracheal instillation of lipopolysaccharide (LPS) in C57BL/6 J mice. The mice were randomly divided into 4 groups of 10. The control group underwent a sham operation and received an equal quantity of saline. The three experimental groups underwent intratracheal instillation of 5 mg/kg LPS, followed by intraperitoneal injection of 4 mg/kg rosiglitazone, 4 mg/kg rosiglitazone plus 1 mg/kg GW9662, or only equal quantity of saline. The histological morphology of the lung, the levels of TNF-α and IL-1β in the bronchoalveolar lavage fluid (BALF), the level of AFC, and the expressions of αENaC and serum and glucocorticoid-induced kinase-1 (SGK1) were determined. Type 2 alveolar (AT II) cells were incubated with rosiglitazone (15 μM) with or without GW9662 (10 μM). The expressions of αENaC and SGK1 were determined 24 h later.ResultsA mouse model of ALI was successfully established. Rosiglitazone significantly ameliorated the lung injury, decreasing the TNF-α and IL-1β levels in the BALF, enhancing AFC, and promoting the expressions of αENaC and SGK1 in ALI mice, which were abolished by the specific PPARγ blocker GW9662. In vitro, rosiglitazone increased the expressions of αENaC and SGK1. This increase was prevented by GW9662.ConclusionsRosiglitazone ameliorated the lung injury and promoted ENaC-mediated AFC via a PPARγ/SGK1-dependent signaling pathway, alleviating pulmonary edema in a mouse model of ALI.

Dataset Information

Acute genome-wide effects of rosiglitazone on PPAR? transcriptional networks in adipocytes.

Publications

Acute genome-wide effects of rosiglitazone on PPARγ transcriptional networks in adipocytes.

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