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• W2094907213 abstract "NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferator-activated receptor-α by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid 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 and an altered fatty acid profile observed in liver-Cpr-null mice. NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferator-activated receptor-α by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid 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 and an altered fatty acid profile observed in liver-Cpr-null mice. NADPH-cytochrome P450 reductase (CPR) 1The abbreviations used are: CPR, NADPH-cytochrome P450 reductase; CYP, cytochrome P450; aRNA, antisense RNA; GO, gene ontology; CAR, constitutive androstane receptor; PPARα, peroxisomal proliferator-activated receptor-α; PXR, pregnane X receptor; FXR, farnesoid X receptor; SREBPs, sterol-response element-binding proteins; HPLC, high performance liquid chromatography. is a microsomal flavoprotein that serves as the electron donor for many enzymes, including all microsomal cytochrome P450 (P450) monooxygenases, the enzymes that metabolize numerous endogenous and exogenous compounds (1Porter T.D. Coon M.J. J. Biol. Chem. 1991; 266: 13469-13472Abstract Full Text PDF PubMed Google Scholar), heme oxygenases (2Schacter B.A. Nelson E.B. Marver H.S. Masters B.S. J. Biol. Chem. 1972; 247: 3601-3607Abstract Full Text PDF PubMed Google Scholar), squalene epoxidase (3Ono T. Bloch K. J. Biol. Chem. 1975; 250: 1571-1579Abstract Full Text PDF PubMed Google Scholar), 7-dehydrocholesterol reductase (4Nishino H. Ishibashi T. Arch. Biochem. Biophys. 2000; 374: 293-298Crossref PubMed Scopus (35) Google Scholar), and cytochrome b5 (5Enoch H.G. Strittmatter P. J. Biol. Chem. 1979; 254: 8976-8981Abstract Full Text PDF PubMed Google Scholar, 6Porter T.D. J. Biochem. Mol. Toxicol. 2002; 16: 311-316Crossref PubMed Scopus (156) Google Scholar). An essential role of CPR-dependent enzymes in fetal development has been demonstrated in germ line Cpr-null mice (7Shen A.L. O'Leary K.A. Kasper C.B. J. Biol. Chem. 2002; 277: 6536-6541Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 8Otto D.M.E. Henderson C.J. Carrie D. Davey M. Gundersen T.E. Blomhoff R. Adams R.H. Tickle C. Wolf C.R. Mol. Cell. Biol. 2003; 23: 6103-6116Crossref PubMed Scopus (160) Google Scholar). In human adults, dysfunctional CPR proteins have been linked to disordered steroidogenesis (9Fluck C.E. Tajima T. Pandey A.V. Arlt W. Okuhara K. Verge C.F. Jabs E.W. Mendonca B.B. Fujieda K. Miller W.L. Nat. Genet. 2004; 36: 228-230Crossref PubMed Scopus (407) Google Scholar). Three mouse strains with modified Cpr alleles were established recently in this laboratory for studying in vivo function of CPR-dependent enzymes. One is the Cpr-lox (Cprlox/lox) mouse, in which the “floxed” Cpr alleles support normal CPR expression (10Wu L. Gu J. Weng Y. Kluetzman K. Swiatek P. Behr M. Zhang Q.Y. Zhuo X.L. Xie Q. Ding X. Genesis. 2003; 36: 177-181Crossref PubMed Scopus (58) Google Scholar); the insertion of the loxP sites did not cause any phenotypic change in the Cpr-lox mice. A derivative of the Cpr-lox mouse is the liver-Cpr-null mouse (Alb-Cre+/-/Cprlox/lox), in which Cpr is deleted specifically in the liver (11Gu J. Weng Y. Zhang Q.Y. Cui H.D. Behr M. Wu L. Yang W.Z. Zhang L. Ding X. J. Biol. Chem. 2003; 278: 25895-25901Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). The adult liver-Cpr-null mouse has a compromised drug metabolism ability, as well as a general induction of multiple hepatic P450 enzymes, a >80% reduction in serum cholesterol level, and an enlarged and fatty liver. Additional phenotypes, including decreases in circulating triglyceride and bile volume, were reported by another group for a similar liver-Cpr-null mouse model (12Henderson C.J. Otto D.M.E. Carrie D. Magnuson M.A. McLaren A.W. Rosewell I. Wolf C.R. J. Biol. Chem. 2003; 278: 13480-13486Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). We have also generated a Cpr-low (Cprlow/low) mouse, in which CPR expression is reduced by 74-95% in all tissues examined (13Wu L. Gu J. Cui H.D. Zhang Q.Y. Behr M. Fang C. Weng Y. Kluetzman K. Swiatek P.J. Yang W.Z. Kaminsky L. Ding X. J. Pharmacol. Exp. Ther. 2005; 312: 35-43Crossref PubMed Scopus (58) Google Scholar). The Cprlow allele was associated with limited embryonic lethality. Female Cpr-low mice were infertile, a phenotype that was likely due, at least in part, to increased serum testosterone and progesterone. Furthermore, adult Cpr-low mice had decreased (by 25-49%) plasma cholesterol and increased expression of many hepatic P450s; these characteristics were found in the liver-Cpr-null mice but to more marked extents. In addition, although some adult Cpr-low mice developed mild centrilobular hepatic lipidosis, none was found to have pathological changes in the liver. These phenotypes, which developed under physiological conditions, reflect the integrated results of the loss of the activities of all hepatic CPR-dependent enzymes in the liver-Cpr-null mice or the suppression of the activities of most CPR-dependent enzymes throughout the body in the Cpr-low mice. Some of the phenotypes, such as the decrease in circulating cholesterol level, can be directly linked to the functions of known CPR-dependent enzymes. However, the causes of other phenotypes, such as the general induction of hepatic P450s in both models and the specific development of fatty liver in the liver-Cpr-null mice, are less clear. A better understanding of the mechanisms underlying these phenotypes will shed light on possible metabolic and associated functional consequences in patients carrying defective CPR alleles. In the present study, genomic analyses of gene expression changes in the livers of the two mouse models were performed. Our goal was to identify mechanisms potentially responsible for the observed hepatic phenotypes in liver-Cpr-null and Cpr-low mice. Hepatic gene expression was analyzed with the Affymetrix Mouse Expression Set 430A GeneChip arrays. The Cpr-lox mouse, which was derived from the same embryonic stem cell that was used to generate the Cpr-low and the liver-Cpr-null mice (10Wu L. Gu J. Weng Y. Kluetzman K. Swiatek P. Behr M. Zhang Q.Y. Zhuo X.L. Xie Q. Ding X. Genesis. 2003; 36: 177-181Crossref PubMed Scopus (58) Google Scholar), was treated as the wild-type control. Genes with expression levels that differed between liver-Cpr-null and Cpr-lox or that differed between Cpr-low and Cpr-lox groups were identified using the criteria of ≥2.0 or ≤0.5 in fold change (change-fold), and p < 0.01. Gene ontology (GO) terms that contained the most significantly changed gene expression were identified through pathway analysis using Gene Map Annotator and Pathway Profiler (www.genmapp.org). A detailed analysis of the gene expression changes in the lipid metabolism and transport pathways led us to propose mechanistic schemes that explain the altered gene expression of multiple P450 enzymes in both mouse models, as well as the severe hepatic lipidosis seen in liver-Cpr-null mice. Additional studies of hepatic fatty acid profiles provided evidence that substantiates the genomic changes in the liver-Cpr-null mice. RNA Preparation and Microarray Hybridization—Protocols for animal breeding and genotyping were reported previously (10Wu L. Gu J. Weng Y. Kluetzman K. Swiatek P. Behr M. Zhang Q.Y. Zhuo X.L. Xie Q. Ding X. Genesis. 2003; 36: 177-181Crossref PubMed Scopus (58) Google Scholar, 11Gu J. Weng Y. Zhang Q.Y. Cui H.D. Behr M. Wu L. Yang W.Z. Zhang L. Ding X. J. Biol. Chem. 2003; 278: 25895-25901Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 13Wu L. Gu J. Cui H.D. Zhang Q.Y. Behr M. Fang C. Weng Y. Kluetzman K. Swiatek P.J. Yang W.Z. Kaminsky L. Ding X. J. Pharmacol. Exp. Ther. 2005; 312: 35-43Crossref PubMed Scopus (58) Google Scholar). Animal use protocols were approved by the Institutional Animal Care and Use Committee of the Wadsworth Center. Animals were maintained at 22 °C with a 12-h on, 12-h off light cycle and were allowed free access to water and a standard laboratory diet. Mice were sacrificed at the age of 2 months. Liver was dissected and was stored at -80 °C until use. Total RNA was prepared from individual liver samples using TRIzol (Invitrogen) and was further purified using Qiagen RNeasy mini columns. The integrity of the RNA preparations was determined by spectrometry and by electrophoretic analysis on agarose gels. Affymetrix Mouse Expression Set 430A GeneChip arrays were used for microarray analysis. Each array contains 22,690 probe sets, representing ∼14,870 distinct genes. Each probe set consists of 11 pairs of 25-mer oligonucleotides. A probe pair is composed of a perfectly matched sequence, which is complementary to the target sequence, and a mismatched sequence, which contains a single nucleotide mismatch at the central base pair position. The mismatched sequence is used as internal control for nonspecific hybridization. Three independent RNA samples were analyzed for each mouse strain (liver-Cpr-null, Cpr-low, and Cpr-lox). Each sample was prepared by pooling equal amounts of total RNA from 2 to 3 mice of the same strain. Five micrograms of total RNA were used for synthesis of biotinylated antisense RNA (aRNA) with MESSAGEAMP™ aRNA kit from Ambion. The labeled aRNA was then fragmented and stored at -20 °C until hybridization. GeneChip array hybridization, staining, and washing were performed according to the Affymetrix GeneChip® Expression Analysis Technical Manual at the Microarray Core Facility of the Wadsworth Center. Briefly, 10 μg of the fragmented aRNA was hybridized to each array at 45 °C for 16 h in a GeneChip® hybridization oven with constant rotation (60 rpm). The arrays were then stained and washed, using the antibody amplification washing and staining protocol (Affymetrix), in a GeneChip Fluidics Station 400. The expression data were collected with a gene array scanner using Affymetrix Microarray Suite version 5.0 (MAS 5.0). Data Analysis—The experimental data sets were normalized using the Robust Multichip Analysis program of the Genetraffic UNO 3.2 software package (Iobion). The hybridizations for control mice were used as the base line. Analysis for significance was performed using the unpaired t test in Genetraffic UNO 3.2 (Iobion). The ratios of averaged values were used to calculate change-fold between two groups. Genes with significantly changed expression were tabulated, along with gene symbol, gene name, transcript identification number, and change-fold values, and were further examined for reproducibility among multiple probe sets for a given gene, where available. Pathway Analysis Using Gene Map Annotator and Pathway Profiler—Two programs, MAPPFinder (14Doniger S.W. Salomonis N. Dahlquist K.D. Vranizan K. Lawlor S.C. Conklin B.R. Genome Biol. 2003; 4: R7.1-R712Crossref Google Scholar) and GenMAPP (version 2.0) (15Dahlquist K.D. Salomonis N. Vranizan K. Lawlor S.C. Conklin B.R. Nat. Genet. 2002; 31: 19-20Crossref PubMed Scopus (809) Google Scholar), were used to group genes having significantly changed expression according to the GO hierarchy at the level of biological processes (GO process), cellular components (GO component), and molecular functions (GO function). The relative extent of gene expression changes in each GO node was compared using the “z score” (15Dahlquist K.D. Salomonis N. Vranizan K. Lawlor S.C. Conklin B.R. Nat. Genet. 2002; 31: 19-20Crossref PubMed Scopus (809) Google Scholar), a standardized difference score, and the number (and percentage) of the genes measured in a GO term that meet user-defined criteria for “significant” changes (e.g.±25% in change-fold and p < 0.01). Redundant GO terms were removed according to the following rules (assuming that term 1 contains more genes than does term 2): if term 1 contains more genes with expression changes than does term 2, then term 2 is removed; however, if the two terms contain the same set of genes with expression changes, then term 1 is removed. Real Time RNA-PCR and Immunoblot Analysis—Real time PCRs were performed according to a protocol described previously (11Gu J. Weng Y. Zhang Q.Y. Cui H.D. Behr M. Wu L. Yang W.Z. Zhang L. Ding X. J. Biol. Chem. 2003; 278: 25895-25901Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar), with gene-specific PCR primers for CYP2A4/5, CYP2B10, CYP4A10, CD36 antigen (CD36), and β-actin. The PCR primers used for CYP2A4/5, CYP2B10, and β-actin were the same as reported (11Gu J. Weng Y. Zhang Q.Y. Cui H.D. Behr M. Wu L. Yang W.Z. Zhang L. Ding X. J. Biol. Chem. 2003; 278: 25895-25901Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). The other primers used were as follows: for CD36, 5′-agtatgtcgtcatgttcc-3′ and 5′-cactataacagctctccaag-3′; for CYP4A10, 5′-agtgtctctgctctaagcc-3′ and 5′-cccaaagaaccagtgaaaag-3′. These primers were designed using Seqweb version 2.1 (Accelrys Inc.). Identities of PCR products were confirmed by electrophoretic analysis on agarose gels (for CYP4A10 and CD36) and sequencing (for CYP4A10). Immunoblot analysis was carried out as described (11Gu J. Weng Y. Zhang Q.Y. Cui H.D. Behr M. Wu L. Yang W.Z. Zhang L. Ding X. J. Biol. Chem. 2003; 278: 25895-25901Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar), with use of rabbit antibodies to CYP2A5 (16Gu J. Zhang Q.Y. Genter M.B. Lipinskas T.W. Negishi M. Nebert D.W. Ding X. J. Pharmacol. Exp. Ther. 1998; 285: 1287-1295PubMed Google Scholar) or rat CPR (BD Biosciences), and goat antibodies to rat CYP1A1/2, CYP2B1, or CYP3A2 (DaiiChi), and monoclonal anti-mouse CD36 (BD Biosciences). Microsomes were prepared according to Coon et al. (17Coon M.J. van der Hoeven T.A. Dahl S.B. Haugen D.A. Methods Enzymol. 1978; 52: 109-117Crossref PubMed Scopus (150) Google Scholar) but without the pyrophosphate washing step. The plasma membrane fraction was prepared according to a protocol described by Zhang and Menon (18Zhang Q.-Y. Menon K.M.J. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 8294-8298Crossref PubMed Scopus (7) Google Scholar). Protein concentration was determined by the bicinchoninic acid method (Pierce) with bovine serum albumin as the standard. Lipid Isolation and Analysis—Livers were excised from 8-week-old mice that had been fed a standard chow diet ad libitum (Prolab® RMH3500). Excised livers were cut into three pieces to provided triplicate samples for analysis and then were frozen at -80 °C until use. For lipid extraction, the Folch method was used (19Folch J. Lee M. Sloane Stanley G.H. J. Biol. Chem. 1957; 226: 497-509Abstract Full Text PDF PubMed Google Scholar). Briefly, tissue sections were homogenized in a Polytron homogenizer (model PT3100) for 30 s at 15,000 -20,000 rpm in chloroform/methanol (2:1) at 20 ml/g liver. The homogenate was shaken for an additional 2 h to fully extract the remaining lipids. After centrifugation and filtration, the extracts were dried down under a stream of nitrogen, and the lipids were resuspended in chloroform. The final lipid samples were split into three equal portions for analysis of complex lipids by high performance liquid chromatography (HPLC), fatty acids by gas chromatography-mass spectroscopy, and total phosphorous determination (20Fiske C.H. Subarrow Y. J. Biol. Chem. 1925; 66: 375-400Abstract Full Text PDF Google Scholar). Complex lipids were separated by using HPLC on a Phenomenex Luna 5-μm silica column developed with a ternary gradient (A, chloroform, methanol, 30% ammonium hydroxide (80:19:1); B, chloroform, methanol, 30% ammonium hydroxide (60:39:1); and C, chloroform, methanol, water, 30% ammonium hydroxide (60:34:5:1) (21Stith B.J. Hall J. Ayres P. Waggoner L. Moore J.D. Shaw W.A. J. Lipid Res. 2000; 41: 1448-1454Abstract Full Text Full Text PDF PubMed Google Scholar). Individual lipid species were detected using an evaporative light scattering detector (Shimadzu-model ELSD-LT). The HPLC system was calibrated with commercial lipid standards (Avanti Polar Lipids and Matreya, LLC). For fatty acid analysis, complex lipids were hydrolyzed with acidified methanol, and the fatty acid methyl esters were purified and analyzed by gas chromatography-mass spectroscopy as described (22Zou Z. DiRusso C.C. Ctrnacta V. Black P.N. J. Biol. Chem. 2002; 277: 31062-31071Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). By using relatively conservative criteria in change-fold (≥2.0 or ≤0.5), and a p value of <0.01, we identified a number of mouse hepatic genes that were differentially expressed between the liver-Cpr-null and control (45 up and 18 down) groups or between the Cpr-low and control (22 up and 26 down) groups. Comparisons of expression levels of these genes among the liver-Cpr-null, Cpr-low, and Cpr-lox (control) groups are shown in Table I, in which the identified genes are grouped in seven functional categories based on GenMAPP and additional literature searches. A number of unknown genes were also identified that have differential expression among the comparison groups.Table IGenes that were differentially expressed in livers of the liver-Cpr-null, Cpr-low, and Cpr-lox mice Genes with significantly changed expression (p < 0.01) and change-fold ≥2.0 or ≤0.5 in the liver-Cpr-null/Cpr-lox or Cpr-low/Cpr-lox comparisons, in at least one probe set and one set of comparisons, are shown. An arbitrary cut-off value (<60) was used to filter genes with very low expression value; probe sets for which none of the three groups has averaged expression values ≥60 were excluded. For genes represented by multiple probe sets, the results for all probe sets are included even though all probe sets may not meet the selection criteria, and the results are arranged in ascending order according to the list of Affymetrix probe set ID numbers. A change-fold value is shown when p < 0.05; otherwise, “no significant change” is assigned. Results from probe sets having <90% homology to target sequence are excluded. For each entry, the reference sequence transcript identification number (RefSeq transcript ID) is given along with the gene symbol and gene name (according to Affymetrix). The genes selected are grouped according to functional categories (defined in MAPP or through literature search).Gene symbolRefSeq transcript IDChange-foldGene nameLiver-Cpr-null/Cpr-loxCpr-low/Cpr-loxLiver-Cpr-null/Cpr-lowBiotransformationCYPsCyp26a1NM_0078113.51.7NCaNC, no significant changeCytochrome P450 26a1Cyp2a4/5NM_0099974.51.9bFold-change values when 0.01 ≤ p < 0.052.4Cytochrome P450 2a4/5Cyp2b20/10NM_00999916.3/15.8/9.15.5/5.8bFold-change values when 0.01 ≤ p < 0.05/3.22.9/2.7/2.8Cytochrome P450 2b10Cyp2c55NM_02808917.22.7bFold-change values when 0.01 ≤ p < 0.056.4Cytochrome P450 2c55Cyp51NM_0200102.2bFold-change values when 0.01 ≤ p < 0.052.2NCCytochrome P450 51Cyp7a1NM_0078243.1/4.9NC/1.9bFold-change values when 0.01 ≤ p < 0.052.5/2.6Cytochrome P450 7a1Cyp2c39NM_010003cRepresentative public ID numbers are shown when a RefSeq transcript ID is not available1.4bFold-change values when 0.01 ≤ p < 0.050.52.9Cytochrome P450 2c39Cyp4a10NM_2016400.7/0.30.4bFold-change values when 0.01 ≤ p < 0.05/0.21.9bFold-change values when 0.01 ≤ p < 0.05/1.5bFold-change values when 0.01 ≤ p < 0.05Cytochrome P450 4a10 (cDNA sequence BC013476)Cyp7b1NM_0078250.3/0.20.5/0.3bFold-change values when 0.01 ≤ p < 0.050.7bFold-change values when 0.01 ≤ p < 0.05/NCCytochrome P450 7b1Non-CYPAldh1a7NM_0119212.51.71.5bFold-change values when 0.01 ≤ p < 0.05Aldehyde dehydrogenase family 1, subfamily A7Ces2NM_1456035.42.32.4Carboxylesterase 2Gsta2NM_0081827.43.52.1bFold-change values when 0.01 ≤ p < 0.05Glutathione S-transferase, Alpha 2 (Yc2)Gsta3NM_0103561.6bFold-change values when 0.01 ≤ p < 0.05/1.6bFold-change values when 0.01 ≤ p < 0.052.3/2.50.7bFold-change values when 0.01 ≤ p < 0.05/NCGlutathione S-transferase, Alpha 3Gstm1NM_0103582.1/2.2/2.2/2.31.6/1.7/1.6bFold-change values when 0.01 ≤ p < 0.05/1.81.3/1.3bFold-change values when 0.01 ≤ p < 0.05/1.3/1.3Glutathione S-transferase, Mu 1Gstm2NM_0081835.22.12.5Glutathione S-transferase, Mu 2Gstm3NM_01035920.04.84.2Glutathione S-transferase, Mu 3Gstm6NM_0081842.42.01.2bFold-change values when 0.01 ≤ p < 0.05Glutathione S-transferase, Mu 6Gstt3NM_1339942.41.5bFold-change values when 0.01 ≤ p < 0.05NCGlutathione S-transferase, Theta 3UgdhNM_0094662.7NC2.0bFold-change values when 0.01 ≤ p < 0.05UDP-glucose dehydrogenase9130231C15RikNM_1339603.61.91.9RIKEN cDNA 9130231C15 geneAI788959NM_1535982.2/1.8NC/NC1.7/1.4bFold-change values when 0.01 ≤ p < 0.05Expressed sequence AI788959Antioxidant and stress responseHmox1NM_0104422.3NC2.3Heme oxygenase (decycling) 1Hsp105NM_0135590.5bFold-change values when 0.01 ≤ p < 0.05/0.4NC/0.4bFold-change values when 0.01 ≤ p < 0.05NC/NCHeat shock protein 105Rad51l1NM_0090140.2/NC0.1/NC1.6bFold-change values when 0.01 ≤ p < 0.05/NCRAD51-like 1 (Saccharomyces cerevisiae)Steroid metabolism and transportAqp8NM_0074743.03.6NCAquaporin 8Dhcr7NM_0078561.9bFold-change values when 0.01 ≤ p < 0.052.1NC7-Dehydrocholesterol reductaseDhcr24NM_0532721.0/NC/2.21.0bFold-change values when 0.01 ≤ p < 0.05/NC/1.6NC/NC/1.324-Dehydrocholesterol reductaseFdpsNM_1344692.9bFold-change values when 0.01 ≤ p < 0.054.8NCFarnesyl-diphosphate synthetaseHmgcs1NM_1459422.9/3.0bFold-change values when 0.01 ≤ p < 0.05/2.9bFold-change values when 0.01 ≤ p < 0.05/NC3.0/2.6/2.7/1.9bFold-change values when 0.01 ≤ p < 0.05NC/NC/NC/NC3-Hydroxy-3-methylglutaryl-coenzyme A synthase 1Idi1NM_145360/NM_1779605.1/3.47.9/4.4NC/NCIsopentenyl-diphosphate δ-isomeraseSc4molNM_0254363.1bFold-change values when 0.01 ≤ p < 0.054.1NCSterol-C4-methyl oxidase-likeSlco1a4NM_0306873.61.4bFold-change values when 0.01 ≤ p < 0.052.6Solute carrier organic anion transporter family, member 1a4SqleNM_0092702.02.4NCSqualene epoxidaseApoa4NM_0074680.2/0.40.2/0.4NC/NCApolipoprotein A-IVHadh2NM_0167630.6bFold-change values when 0.01 ≤ p < 0.05/0.60.5/0.6NC/NCHydroxyacyl-coenzyme A dehydrogenase type IIHsd3b5NM_0082950.2NCNCHydroxysteroid dehydrogenase-5, δ<5>-3-β2610207I16RikNM_024255NC/0.60.6bFold-change values when 0.01 ≤ p < 0.05/0.5NC/NCRIKEN cDNA 2610207I16 geneTriglyceride and fatty acid metabolism and transportCd36NM_0076433.2/2.8NC/NC3.2/3.0CD36 antigenLplNM_0085092.1/1.5bFold-change values when 0.01 ≤ p < 0.051.3/NC1.6/NCLipoprotein lipaseScd1NM_0091272.4bFold-change values when 0.01 ≤ p < 0.05/1.8bFold-change values when 0.01 ≤ p < 0.053.0bFold-change values when 0.01 ≤ p < 0.05/2.3NC/NCStearoyl-coenzyme A desaturase 1Cte/Mte1NM_012006/NM_1341880.5bFold-change values when 0.01 ≤ p < 0.05/0.6bFold-change values when 0.01 ≤ p < 0.050.2/0.22.9/2.7Cytosolic acyl-CoA thioesterase 1/Mitochondrial acyl-CoA thioesterase 1EhhadhNM_0237370.40.21.8bFold-change values when 0.01 ≤ p < 0.05Enoyl-coenzyme A, Hydratase/3-hydroxyacyl coenzyme A dehydrogenaseElovl5NM_1342550.7bFold-change values when 0.01 ≤ p < 0.05/0.7bFold-change values when 0.01 ≤ p < 0.050.5/0.51.5bFold-change values when 0.01 ≤ p < 0.05/1.5ELOVL family member 5, elongation of long chain fatty acids (yeast)Fabp2NM_0079800.30.4NCFatty acid-binding protein 2, intestinalMgllNM_011844NC/NC/NC/NC0.5/NC/0.5/0.7bFold-change values when 0.01 ≤ p < 0.051.7/NC/1.5/1.6Monoglyceride lipaseCarbohydrate and amino acid metabolismAsnsNM_012055NC/3.3NC/NC4.4bFold-change values when 0.01 ≤ p < 0.05/4.0Asparagine synthetaseCsadNM_1449422.71.4bFold-change values when 0.01 ≤ p < 0.051.9Cysteine sulfinic acid decarboxylaseGckNM_0102921.2bFold-change values when 0.01 ≤ p < 0.05/1.5bFold-change values when 0.01 ≤ p < 0.051.7/2.70.7/0.5GlucokinasePgdNM_0258011.8/2.2/2.2/1.9NC/1.4bFold-change values when 0.01 ≤ p < 0.05/1.5bFold-change values when 0.01 ≤ p < 0.05/1.3bFold-change values when 0.01 ≤ p < 0.05NC/1.6/1.5bFold-change values when 0.01 ≤ p < 0.05/1.4Phosphogluconate dehydrogenaseBdhNM_1751770.5/0.5NC/0.7bFold-change values when 0.01 ≤ p < 0.050.6/0.7bFold-change values when 0.01 ≤ p < 0.053-Hydroxybutyrate dehydrogenase (heart, mitochondrial)SdsNM_1455650.5NC0.5Serine dehydrataseGrowth and signal transductionGadd45bNM_0086554.3/1.7NC/NC4.5/1.8Growth arrest and DNA-damage-inducible 45 βLgals1NM_0084951.9/3.6NC/NC1.8/3.4Lectin, galactose-binding, soluble 1Atf5NM_030693/NM_0333690.50.4NCActivating transcription factor 5Fgf1NM_0101970.4/0.60.7bFold-change values when 0.01 ≤ p < 0.05/0.8bFold-change values when 0.01 ≤ p < 0.050.6/0.7bFold-change values when 0.01 ≤ p < 0.05Fibroblast growth factor 1GrnNM_008175NC/NC/0.9bFold-change values when 0.01 ≤ p < 0.050.5/0.5/0.61.7bFold-change values when 0.01 ≤ p < 0.05/1.9/1.6GranulinRsb30NM_0294940.50.3NCRAB30, member RAS oncogene familyOthersActg1NM_0096092.60.7bFold-change values when 0.01 ≤ p < 0.054.0Actin, γ, cytoplasmic 1Antxr2NM_1337382.3NC2.0bFold-change values when 0.01 ≤ p < 0.05Anthrax toxin receptor 2Anxa5NM_0096732.50.83.4Annexin A5Cldn3NM_0099022.2/1.4/1.7/1.5NC/NC/NC/NC1.8/1.3bFold-change values when 0.01 ≤ p < 0.05/1.6/1.4Claudin 3Entpd5NM_0076472.0/1.5/2.0/2.4NC/NC/NC/1.2bFold-change values when 0.01 ≤ p < 0.051.9/1.5/2.1/2.0Ectonucleoside triphosphate diphosphohydrolase 5Ethe1NM_0231542.1bFold-change values when 0.01 ≤ p < 0.052.9NCEthylmalonic encephalopathy 1PrnpNM_0111701.4bFold-change values when 0.01 ≤ p < 0.05/2.2NC/NC1.2bFold-change values when 0.01 ≤ p < 0.05/1.6bFold-change values when 0.01 ≤ p < 0.05Prion proteinTcea3NM_011542NC2.20.5Transcription elongation factor A (SII), 31810044O22RikNM_0255581.6/2.0bFold-change values when 0.01 ≤ p < 0.05/NC/2.22.3/2.6bFold-change values when 0.01 ≤ p < 0.05/NC/2.10.7/NC/NC/NCRIKEN cDNA 1810044O22 geneCcrn4lNM_0098340.4/0.8bFold-change values when 0.01 ≤ p < 0.05/0.8bFold-change values when 0.01 ≤ p < 0.05NC/NC/NC0.4/0.9bFold-change values when 0.01 ≤ p < 0.05/NCCCR4 carbon catabolite repression 4-like (S. cerevisiae)Dhrs8NM_0532620.5/0.7bFold-change values when 0.01 ≤ p < 0.050.5/0.7NC/NCDehydrogenase/reductase (SDR family) member 8Fgl1NM_145594NC0.32.3Fibrinogen-like protein 1MtapNM_024433NC/NC/0.9bFold-change values when 0.01 ≤ p < 0.05/NC0.6/0.9bFold-change values when 0.01 ≤ p < 0.05/0.8/0.51.4/1.1bFold-change values when 0.01 ≤ p < 0.05/1.1bFold-change values when 0.01 ≤ p < 0.05/1.8bFold-change values when 0.01 ≤ p < 0.05Methylthioadenosine phosphorylaseNat6NM_019750NC/0.6NC/0.5NC/NCN-Acetyltransferase 6Sdc4NM_011521NC/0.5NC/0.60.5bFold-change values when 0.01 ≤ p < 0.05/NCSyndecan 4Serpina3kNM_0114580.9bFold-change values when 0.01 ≤ p < 0.05/0.3NC/NCNC/NCSerine (or cysteine) proteinase inhibitor, clade A, member 3KSlc22a5NM_011396NC/0.7bFold-change values when 0.01 ≤ p < 0.05NC/0.5NC/1.5bFold-change values when 0.01 ≤ p < 0.05Solute carrier family 22 (organic cation transporter), member 5Vnn1NM_0117040.50.23.1bFold-change values when 0.01 ≤ p < 0.05Vanin 1Unknown0610011I04RikNM_0253262.1/1.6NC/NC1.9/1.4RIKEN cDNA 0610011I04 gene1110067D22RikNM_1737521.3/2.2NC/NC1.4/2.0RIKEN cDNA 1110067D22 gene1810014L12RikNM" @default.
• W2094907213 created "2016-06-24" @default.
• W2094907213 creator A5009018339 @default.
• W2094907213 creator A5010022627 @default.
• W2094907213 creator A5013765814 @default.
• W2094907213 creator A5066286105 @default.
• W2094907213 creator A5078223796 @default.
• W2094907213 date "2005-09-01" @default.
• W2094907213 modified "2023-10-07" @default.
• W2094907213 title "Hepatic Gene Expression Changes in Mouse Models with Liver-specific Deletion or Global Suppression of the NADPH-Cytochrome P450 Reductase Gene" @default.
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• W2094907213 doi "https://doi.org/10.1074/jbc.m504447200" @default.
• W2094907213 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16006652" @default.
• W2094907213 hasPublicationYear "2005" @default.
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