Project description:The nuclear receptor CAR (constitutive androstane receptor) mediates the effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on gene transcription. To investigate the relative role of CAR and also PXR in the induction response, cDNA arrays were generated containing 120 (Sterolgene V1) genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with TCPOBOP for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments show the complex role of CAR receptor in the expression of genes involved in drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 10mg/kg TCPOBOP or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the TCPOBOP treated ones and hybridized to Sterolgene V1 arrays.
Project description:The nuclear receptor PXR (Pregnane X rreceptor) mediates the effects of pregnenolone-16alpha-carbonitrile (PCN) on gene transcription. The relative role of PXR and also CAR to the induction response by PCN was studied on cDNA arrays containing 320 (Steroltalk V2) genes (genes involved in cyrcadian rhythm, drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PCN for gene expression within the European Framework V program âSteroltalkâ (www.steroltalk.net). Results from these experiments show the complex role of PXR receptor in the expression of genes involved in cyrcadian rhythm, drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 40mg/kg PCN or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the PCN treated ones and hybridized to Steroltalk V2 arrays.
Project description:This SuperSeries is composed of the following subset Series: GSE12489: Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis GSE12509: Effect of TCPOBOP on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis Refer to individual Series
Project description:The nuclear receptor PXR (Pregnane X rreceptor) mediates the effects of pregnenolone-16alpha-carbonitrile (PCN) on gene transcription. The relative role of PXR and also CAR to the induction response by PCN was studied on cDNA arrays containing 320 (Steroltalk V2) genes (genes involved in cyrcadian rhythm, drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PCN for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments show the complex role of PXR receptor in the expression of genes involved in cyrcadian rhythm, drug metabolism and cholesterol biosynthesis.
Project description:The nuclear receptor CAR (constitutive androstane receptor) mediates the effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on gene transcription. To investigate the relative role of CAR and also PXR in the induction response, cDNA arrays were generated containing 120 (Sterolgene V1) genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with TCPOBOP for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments show the complex role of CAR receptor in the expression of genes involved in drug metabolism and cholesterol biosynthesis.
Project description:TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene) and PCN (pregnenolone 16α-carbonitrile) are inducers of drug metabolism through activation of nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor), respectively. Mouse experiment was designed to study the effect of CAR and PXR activation on cholesterol homeostasis genes and other genes, which are present on the Steroltalk v2 microarray. Treatments were combined with standard and high-cholesterol diet to observe the interference of high liver cholesterol on nuclear receptor transcription regulation. All experiments were done within the European sixth Framework program âSteroltalkâ (www.steroltalk.net). Results form these experiments give new knowledge about involvement of âxenosensorsâ CAR and PXR in regulation of endogenous liver metabolism. Animals were injected i.p. 3mg/kg TCPOBOP, 40 mg/kg PCN or vehicle (corn oil) in combination of one week of standard or 1% cholesterol diet prior tretament. After 24h they were sacrificed and total RNA was isolated from the livers. Each sample was hybridized with a reference sample to Steroltalk v2 microarrays.
Project description:Several drugs induce liver steatosis through pregnane X receptor (PXR)-mediated mechanism. Atorvastatin is a PXR ligand but is still safe even in patients with metabolic dysfunction-associated steatotic liver disease. To reveal differences between atorvastatin and other PXR ligands, we characterized the effect of atorvastatin on PXR-mediated gene regulation and liver steatosis in mice. Mice were treated orally with atorvastatin, a classical PXR ligand pregnenolone 16α-carbonitrile (PCN), or pravastatin, a statin not activating PXR. Atorvastatin treatment was also performed in PXR knockout mice. Analysis of liver transcriptomics after four-day treatment indicated that atorvastatin regulates genes almost exclusively through PXR. Atorvastatin and PCN regulated partially overlapping, but distinct set of genes and Cyp3a11 was not induced by atorvastatin. Pathway analysis indicated that the atorvastatin treatment predominantly induced genes involved in cholesterol synthesis, while PCN affected pathways involved in growth, proliferation, and steatosis. PCN increased nuclear SREBP1 protein level while atorvastatin increased both SREBP1 and SREBP2. In high-fat diet (HFD)-fed mice, 28-day oral treatment with PCN aggravated diet-induced liver steatosis while atorvastatin had no effect. 28-day atorvastatin treatment reduced the hepatic expression of PXR, and its effect on cholesterol synthesis genes disappeared. PCN did not influence PXR expression, and the Cyp3a11 expression remained induced still after 28 days. Among the lipogenic genes studied, Scd1 was the only one significantly induced by PCN after 28-day treatment in the HFD-fed mice. In summary, atorvastatin regulates mouse liver transcriptomics PXR dependently but differently from PCN and represses PXR in long-term treatment in the HFD-fed mice. Unlike PCN, atorvastatin does not promote liver steatosis.
Project description:Changes in gene expression were assayed in mouse liver nuclear RNA following a single injection of the CAR agonist TCPOBOP (1,4-Bis-[2-(3,5-dichloropyridyloxy)]benzene) or the PXR agonist PCN (pregnenolone 16α-carbonitrile) in 7-week old mice. This study is part of a larger study entitled Sex-Differential Responses of Tumor Promotion-Associated Genes and Dysregulation of Novel Long Noncoding RNAs in Constitutive Androstane Receptor-Activated Mouse Liver (PMID: 28903501).
Project description:Several drugs induce liver steatosis through pregnane X receptor (PXR)-mediated mechanism. Atorvastatin is a PXR ligand but is still safe even in patients with metabolic dysfunction-associated steatotic liver disease. To reveal differences between atorvastatin and other PXR ligands, we characterized the effect of atorvastatin on PXR-mediated gene regulation and liver steatosis in mice. Mice were treated orally with atorvastatin, a classical PXR ligand pregnenolone 16α-carbonitrile (PCN), or pravastatin, a statin not activating PXR. Atorvastatin treatment was also performed in PXR knockout mice. Analysis of liver transcriptomics after four-day treatment indicated that atorvastatin regulates genes almost exclusively through PXR. Atorvastatin and PCN regulated partially overlapping, but distinct set of genes and Cyp3a11 was not induced by atorvastatin. Pathway analysis indicated that the atorvastatin treatment predominantly induced genes involved in cholesterol synthesis, while PCN affected pathways involved in growth, proliferation, and steatosis. PCN increased nuclear SREBP1 protein level while atorvastatin increased both SREBP1 and SREBP2. In high-fat diet (HFD)-fed mice, 28-day oral treatment with PCN aggravated diet-induced liver steatosis while atorvastatin had no effect. 28-day atorvastatin treatment reduced the hepatic expression of PXR, and its effect on cholesterol synthesis genes disappeared. PCN did not influence PXR expression, and the Cyp3a11 expression remained induced still after 28 days. Among the lipogenic genes studied, Scd1 was the only one significantly induced by PCN after 28-day treatment in the HFD-fed mice. In summary, atorvastatin regulates mouse liver transcriptomics PXR dependently but differently from PCN and represses PXR in long-term treatment in the HFD-fed mice. Unlike PCN, atorvastatin does not promote liver steatosis.
Project description:PXR deficient mice were fed high-fat diet (HFD) and treated with PCN, a selective murine PXR agonist, and hepatic effects of the high-fat diet feeding and PCN treatment were studied.