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Altered gene expression in the small intestine of IE-Cpr-null mice

ABSTRACT: The NADPH-cytochrome P450 reductase (CPR) is essential for the functioning of microsomal cytochrome P450 (P450) monoxygenases. The biological functions of the CPR-dependent enzymes in the intestine are not known, despite the vast knowledge available on the biochemical properties of the various oxygenases. A mouse model with intestinal epithelium (IE)-specific Cpr-knockout (IE-Cpr-null) was recently generated in this laboratory (Zhang et al., Drug Metab. Dispos., 37, 651-657, 2009). The IE-Cpr-null mice did not display any obvious abnormalities in growth, development, or reproduction, and their intestines appeared to have a normal structure. Despite the absence of observable phenotypes, we hypothesized that loss of the enterocyte CPR expression will impact homeostasis of endogenous compounds, and expression of genes, that have critical biological function in the small intestine. In the present study, we have performed genomic analyses for enterocytes from IE-Cpr-null mice and their wild-type littermates, using Affymetrix Mouse Expression Set 430A 2.0 GeneChip Arrays. Our aim was to identify small intestinal gene-expression changes, which may shed light on potential biological roles of CPR and CPR-dependent enzymes in the small intestine. Our analysis revealed significant expression increases in P450s, transporters, cholesterol biosynthesis, and (unexpectedly) antigen presentation/processing. Further genomic and biochemical analyses revealed potential mechanisms linking CPR-dependent enzymes and the expression of major histocompatibility complex class II genes in the small intestine.

ORGANISM(S): Mus musculus

PROVIDER: GSE35293 | GEO | 2012/04/11

SECONDARY ACCESSION(S): PRJNA151595

REPOSITORIES: GEO

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Altered gene expression in the small intestine of IE-Cpr-null mice

Project description:The NADPH-cytochrome P450 reductase (CPR) is essential for the functioning of microsomal cytochrome P450 (P450) monoxygenases. The biological functions of the CPR-dependent enzymes in the intestine are not known, despite the vast knowledge available on the biochemical properties of the various oxygenases. A mouse model with intestinal epithelium (IE)-specific Cpr-knockout (IE-Cpr-null) was recently generated in this laboratory (Zhang et al., Drug Metab. Dispos., 37, 651-657, 2009). The IE-Cpr-null mice did not display any obvious abnormalities in growth, development, or reproduction, and their intestines appeared to have a normal structure. Despite the absence of observable phenotypes, we hypothesized that loss of the enterocyte CPR expression will impact homeostasis of endogenous compounds, and expression of genes, that have critical biological function in the small intestine. In the present study, we have performed genomic analyses for enterocytes from IE-Cpr-null mice and their wild-type littermates, using Affymetrix Mouse Expression Set 430A 2.0 GeneChip Arrays. Our aim was to identify small intestinal gene-expression changes, which may shed light on potential biological roles of CPR and CPR-dependent enzymes in the small intestine. Our analysis revealed significant expression increases in P450s, transporters, cholesterol biosynthesis, and (unexpectedly) antigen presentation/processing. Further genomic and biochemical analyses revealed potential mechanisms linking CPR-dependent enzymes and the expression of major histocompatibility complex class II genes in the small intestine. Adult (2.5-3.0 month-old) male IE-Cpr-null and WT litermates were used for all experiments. RNA was collected from eight mice of each genotype and RNA from two mice of the same genotype was pooled prior to hybridization to the microarray to create a total of four samples for each genotype.

2012-04-10 | E-GEOD-35293 | biostudies-arrayexpress

Altered hepatic gene expression in liver-Cpr-null and Cpr-low mice

Project description:NADPH-cytochrome P450 reductase (CPR) is important for the functions of many enzymes, such as microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. Two mouse models with deficient CPR expression in adults were recently generated in this laboratory: liver-Cpr-null (with liver-specific Cpr deletion) (Gu et al., J. Biol. Chem., 278, 25895–25901, 2003) and Cpr-low (with reduced CPR expression in all organs examined) (Wu et al. J. Pharmacol. Expt. Ther. 312, 35-43, 2005). The phenotypes included a reduced serum cholesterol level and an induction of hepatic P450 in both models, and hepatomegaly and fatty liver in the liver-Cpr-null mouse alone. Our aim was to identify hepatic gene-expression changes related to these phenotypes. Cpr-lox mice, which have normal CPR expression (Wu et al., Genesis, 36, 177-181, 2003.), were used as the control in microarray analysis. A detailed analysis of the gene-expression changes in lipid metabolism and transport pathways revealed potential mechanisms, such as an increased activation of constitutive androstane receptor (CAR) and a decreased activation of peroxisomal proliferators activated receptor alpha (PPAR-gamma) by precursors of cholesterol biosynthesis, that underlie common changes (e.g., induction of multiple P450s and inhibition of genes for fatty acids metabolism) in response to CPR-loss in the two mouse models. Moreover, we also uncovered model-specific gene-expression changes, such as the induction of a lipid translocase (CD36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (CPT1a) and acyl-CoA synthetase long-chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis observed in liver-Cpr-null, but not Cpr-low mice. Keywords = Cytochrome P450 Keywords = NADPH-cytochrome P450 reductase Keywords = transgenic mice Keywords = liver Keywords = nuclear receptor Keywords: other

2005-07-16 | GSE2362 | GEO

Transcription profiling of mouse models with liver-specific deletion or global hypomorphic expression of the NADPH-cytochrome P450 reductase gene to study molecular mechanisms for the regulation of microsomal cytochrome P450 and the fatty liver phenotype.

Project description:NADPH-cytochrome P450 reductase (CPR) is important for the functions of many enzymes, such as microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. Two mouse models with deficient CPR expression in adults were recently generated in this laboratory: liver-Cpr-null (with liver-specific Cpr deletion) (Gu et al., J. Biol. Chem., 278, 25895-25901, 2003) and Cpr-low (with reduced CPR expression in all organs examined) (Wu et al. J. Pharmacol. Expt. Ther. 312, 35-43, 2005). The phenotypes included a reduced serum cholesterol level and an induction of hepatic P450 in both models, and hepatomegaly and fatty liver in the liver-Cpr-null mouse alone. Our aim was to identify hepatic gene-expression changes related to these phenotypes. Cpr-lox mice, which have normal CPR expression (Wu et al., Genesis, 36, 177-181, 2003.), were used as the control in microarray analysis. A detailed analysis of the gene-expression changes in lipid metabolism and transport pathways revealed potential mechanisms, such as an increased activation of constitutive androstane receptor (CAR) and a decreased activation of peroxisomal proliferators activated receptor alpha (PPARï?¡) by precursors of cholesterol biosynthesis, that underlie common changes (e.g., induction of multiple P450s and inhibition of genes for fatty acids metabolism) in response to CPR-loss in the two mouse models. Moreover, we also uncovered model-specific gene-expression changes, such as the induction of a lipid translocase (CD36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (CPT1a) and acyl-CoA synthetase long-chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis observed in liver-Cpr-null, but not Cpr-low mice.

2007-08-31 | E-GEOD-2362 | biostudies-arrayexpress

Effect of Cyp3a-cluster knockout on small intestine

Project description:Analysis of small intestine with or without Cytochrome P450 (Cyp) 3a-cluster. Cyp3a family is one of the most important enzymes for drug metabolism. These results suggest the biological effects of Cyp3a-knockout on small intestine.

2018-11-15 | GSE103534 | GEO

Hepatic reductase null

Project description:Microarray analysis to examine the relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (CPR) null mice. Keywords: ordered

2004-07-11 | GSE1468 | GEO

Transcription profiling of mouse P458 reductase (CPR) animals

Project description:Microarray analysis to examine the relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (CPR) null mice.

2008-06-11 | E-GEOD-1468 | biostudies-arrayexpress

Mus musculus

Project description:Altered gene expression in the small intestine of IE-Cpr-null mice

| PRJNA151595 | ENA

Identification of SpySystem-linked CYP73A5-ATR2 by LC-MSMS

Project description:Eukaryotic cytochrome P450 enzymes, generally colocalizing with their redox partner cytochrome P450 reductase (CPR) on the cytoplasmic surface of organelle membranes, often perform poorly in prokaryotic cells, whether expressed with CPR as a tandem chimera or free-floating individuals, causing a low titer of heterologous chemicals. To improve their biosynthetic performance in Escherichia coli, we here architecturally design self-assembled alternatives of eukaryotic P450 system using reconstructed P450 and CPR, and create a set of N-termini-bridged P450-CPR heterodimers as the counterparts of eukaryotic P450 system with N-terminus-guided colocalization. The covalent counterparts show superior and robust biosynthetic performance; the N-termini-bridged architecture is validated to improve the biosynthesis of both plant and human P450 systems. Furthermore, the architectural configuration of protein assemblies has an inherent effect on the biosynthesis of N-termini-bridged P450-CPR heterodimers. The results suggest that spatial architecture-guided protein assembly could serve as an efficient strategy for improving the biosynthesis of protein complexes, particularly those related to eukaryotic membranes, in prokaryotic and even eukaryotic hosts.

2024-10-29 | PXD056539 | Pride

Identification of SpySystem-linked CYP73A5-ATR2 by LC-MSMS

2024-10-04 | PXD056592 |

Increased carvone production in Escherichia coli by balancing limonene conversion enzyme expression via targeted quantification concatamer proteome analysis

Project description:The cytochrome P450 limonene-6-hydroxylase (P450), cytochrome P450 reductase (CPR) and carveol dehydrogenase (CDH) were expressed in Escherichia coli for (−)-carvone production from (−)-limonene. The optimum ratio of enzyme expression to maximize (−)-carvone production was determined using the proteome analysis quantification concatamer (QconCAT) method.

2022-08-24 | PXD028077 | JPOST Repository

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