Identification of Chemical Modulators of the Constitutive Activated Receptor (CAR) in a Gene Expression Compendium

The nuclear receptor family member constitutive activated receptor (CAR) is activated by structurally diverse drugs and environmentally-relevant chemicals leading to transcriptional regulation of genes involved in xenobiotic metabolism and transport. Chronic activation of CAR increases liver cancer incidence in rodents, whereas suppression of CAR can lead to steatosis and insulin insensitivity. Here, analytical methods were developed to screen for chemical treatments in a gene expression compendium that lead to alteration of CAR activity. A gene expression biomarker signature of 83 CAR-dependent genes was identified using microarray profiles from the livers of wild-type and CAR-null mice after exposure to three structurally-diverse CAR activators (CITCO, phenobarbital, TCPOBOP). A rank-based algorithm (Running Fisher's algorithm (p-value < 10-4)) was used to evaluate the similarity between the CAR biomarker signature and a test set of 28 and 32 comparisons positive or negative, respectively, for CAR activation; the test resulted in a balanced accuracy of 97%. The biomarker signature was used to identify chemicals that activate or suppress CAR in an annotated mouse liver/primary hepatocyte gene expression database of ∼1850 comparisons. CAR was activated by 1) activators of the aryl hydrocarbon receptor (AhR) in wild-type but not AhR-null mice, 2) pregnane X receptor (PXR) activators in wild-type and to lesser extents in PXR-null mice, and 3) activators of PPARα in wild-type and PPARα-null mice. CAR was consistently activated by five conazole fungicides and four perfluorinated compounds. Comparison of effects in wild-type and CAR-null mice showed that the fungicide propiconazole increased liver weight and hepatocyte proliferation in a CAR-dependent manner, whereas the perfluorinated compound perfluorooctanoic acid (PFOA) increased these endpoints in a CAR-independent manner. A number of compounds suppressed CAR coincident with increases in markers of inflammation including acetaminophen, concanavalin A, lipopolysaccharide, and 300 nm silica particles. In conclusion, we have shown that a CAR biomarker signature coupled with a rank-based similarity method accurately predicts CAR activation. This analytical approach, when applied to a gene expression compendium, increased the universe of known chemicals that directly or indirectly activate CAR, highlighting the promiscuous nature of CAR activation and signaling through activation of other xenobiotic-activated receptors.

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Comparative Gene Expression Profiles Following UV Exposure in Wild-Type and SOS-Deficient Escherichia coli

Genetics ◽

10.1093/genetics/158.1.41 ◽

2001 ◽

Vol 158 (1) ◽

pp. 41-64 ◽

Cited By ~ 12

Author(s):

Justin Courcelle ◽

Arkady Khodursky ◽

Brian Peter ◽

Patrick O Brown ◽

Philip C Hanawalt

Keyword(s):

Gene Expression ◽

Escherichia Coli ◽

Uv Irradiation ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Uv Exposure ◽

Dependent Manner ◽

Wild Type ◽

Independent Manner ◽

E Coli

Abstract The SOS response in UV-irradiated Escherichia coli includes the upregulation of several dozen genes that are negatively regulated by the LexA repressor. Using DNA microarrays containing amplified DNA fragments from 95.5% of all open reading frames identified on the E. coli chromosome, we have examined the changes in gene expression following UV exposure in both wild-type cells and lexA1 mutants, which are unable to induce genes under LexA control. We report here the time courses of expression of the genes surrounding the 26 documented lexA-regulated regions on the E. coli chromosome. We observed 17 additional sites that responded in a lexA-dependent manner and a large number of genes that were upregulated in a lexA-independent manner although upregulation in this manner was generally not more than twofold. In addition, several transcripts were either downregulated or degraded following UV irradiation. These newly identified UV-responsive genes are discussed with respect to their possible roles in cellular recovery following exposure to UV irradiation.

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Acute Iron Dextran Injection Increases Liver Weight and Reduces Glycerol Kinase Expression in Liver

Indonesian Journal of Clinical Pharmacy ◽

10.15416/ijcp.2018.7.4.236 ◽

2018 ◽

Vol 7 (4) ◽

pp. 236

Author(s):

Ramdan Panigoro ◽

Fadhal M. Ahmad ◽

Uni Gamayani ◽

Neni Anggraeni ◽

Rini Widyastuti ◽

...

Keyword(s):

Gene Expression ◽

Iron Overload ◽

Liver Weight ◽

Glycerol Kinase ◽

Dependent Manner ◽

Iron Dextran ◽

Kinase Gene ◽

Imagej Software ◽

Kinase Expression ◽

Dose Dependent

Iron is essential and needed in a very small amount. When iron exceeds normal need, metabolic alteration occurs, causing hepatosteatosis. The mechanism of iron inducing hepatosteatosis remains unclear. Glycerol kinase, the enzyme responsible in triglyceride synthesis initiation, is assumed to have a role in the pathomechanism of hepatosteatosis. This study aimed to investigate the gene expression of glycerol kinase in an acute iron overload condition. This study was conducted in Animal Laboratory Faculty of Medicine and Central Laboratory Universitas Padjadjaran from May to June 2017. Three groups of mice were divided by the dose of iron dextran injection (0, 0.1, 0.3 mg/day/mice). After 19 days, mice were terminated, liver weight was measured and glycerol kinase gene expression in the liver was determined by semi-qualitative PCR. Quantification of PCR result was calculated by ImageJ software. There was a significant change in liver weight of the mice in a dose-dependent manner of iron injection. The expression of glycerol kinase tended to decrease, but statistically insignificant. Acute iron dextran injection increases liver weight and tends to reduce glycerol kinase gene expression in mice liver.Keywords: Glycerol kinase, hepatosteatosis, iron overload Efek Zat Besi Dosis Tinggi Akut dalam Meningkatkan Berat Organ dan Menurunkan Ekspresi Gliserol Kinase HeparAbstrakZat besi merupakan nutrien esensial dan diperlukan dalam jumlah yang sangat kecil. Ketika kadar zat besi melebihi kadar normal dalam tubuh, terjadi perubahan metabolisme yang menyebabkan hepatosteatosis. Mekanisme zat besi dalam menyebabkan hepatosteatosis masih belum diketahui secara pasti. Gliserol kinase, enzim yang menginisiasi sintesis trigliserida, diduga berperan dalam patomekanisme hepatosteatosis. Penelitian ini bertujuan untuk meneliti ekspresi gen gliserol kinase pada hepar pada kondisi tinggi zat besi akut. Penelitian ini dilakukan di Laboratorium Hewan Fakultas Kedokteran dan Laboratorium Sentral Universitas Padjadjaran dari bulan Mei sampai dengan Juni 2017. Tiga kelompok mencit dibagi berdasarkan dosis injeksi iron dextran intraperitoneal (0, 0,1, 0,3 mg/hari/ekor). Setelah 19 hari, mencit diterminasi, berat hepar ditimbang dan ekspresi gen gliserol kinase diukur dengan metode semi-kualitatif PCR. Kuantifikasi hasil PCR dilakukan dengan menggunakan aplikasi ImageJ. Terdapat peningkatan berat hepar secara signifikan yang sejalan dengan dosis ijeksi zat besi. Ekspresi gen gliserol kinase cenderung menurun, meskipun secara statistik tidak signifikan. Keadaan tinggi kadar zat besi yang akut meningkatkan berat hepar dan cenderung menurunkan ekspresi gen gliserol kinase pada hepar mencit.Kata kunci: Gliserol kinase, hepatosteatosis, zat besi berlebih

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Comparison of the Hepatic Effects of Phenobarbital in Chimeric Mice Containing Either Rat or Human Hepatocytes With Humanized Constitutive Androstane Receptor and Pregnane X Receptor Mice

Toxicological Sciences ◽

10.1093/toxsci/kfaa125 ◽

2020 ◽

Vol 177 (2) ◽

pp. 362-376

Author(s):

Tomoya Yamada ◽

Ayako Ohara ◽

Naoya Ozawa ◽

Keiko Maeda ◽

Miwa Kondo ◽

...

Keyword(s):

Gene Expression ◽

Liver Tumor ◽

Constitutive Androstane Receptor ◽

Pregnane X Receptor ◽

Rat Hepatocytes ◽

Global Gene Expression ◽

Human Hepatocytes ◽

Chimeric Mouse ◽

Chimeric Mice ◽

Wild Type

Abstract Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, because rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild-type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/β-catenin signaling when compared with those of hCAR/hPXR mice, wild-type mice, and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators whereas the hCAR/hPXR mouse is not.

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Modulation of Virulence by Two Acidified Nitrite-Responsive Loci of Salmonella enterica Serovar Typhimurium

Infection and Immunity ◽

10.1128/iai.71.6.3196-3205.2003 ◽

2003 ◽

Vol 71 (6) ◽

pp. 3196-3205 ◽

Cited By ~ 39

Author(s):

Charles C. Kim ◽

Denise Monack ◽

Stanley Falkow

Keyword(s):

Salmonella Enterica ◽

Fluorescent Protein ◽

Dependent Manner ◽

Wild Type ◽

Independent Manner ◽

Inducible Promoters ◽

Serovar Typhimurium ◽

Bacterial Genes ◽

Green Fluorescent

ABSTRACT Two acidified nitrite-inducible genes of Salmonella enterica serovar Typhimurium were identified with a green fluorescent protein-based promoter-trap screen. The nitrite-inducible promoters were located upstream of loci that we designated nipAB and nipC, which correspond to hcp-hcr (hybrid cluster protein) of Escherichia coli and norA of Alcaligenes eutrophus, respectively. Maximal induction of the promoters by nitrite was dependent on pH. The nipAB promoter was regulated by oxygen in an Fnr-dependent manner. The nipC promoter was also regulated by oxygen but in an Fnr-independent manner. The promoters were upregulated in activated RAW264.7 macrophage-like cells, which produce NO via the inducible nitric oxide synthase (iNOS), and the induction was inhibited by aminoguanidine, an inhibitor of iNOS. Although the nipAB and nipC mutants displayed no defects under a variety of in vitro conditions or in tissue culture infections, they exhibited lower oral 50% lethal doses (LD50s) than did the wild type in C57BL/6J mouse infections. The lower LD50s reflected an unexpected increased ability of small inoculating doses of the mutant bacteria to cause lethal infection 2 to 3 weeks after challenge, compared to a similar challenge dose of wild-type bacteria. We conclude that these genes are regulated by physiological nitrogen oxides and that the absence of these bacterial genes in some way diminishes the ability of mice to clear a low dose infection.

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Diabetes induced decreases in PKA signaling in cardiomyocytes: the role of insulin

10.1101/2020.04.02.021667 ◽

2020 ◽

Author(s):

Craig A. Eyster ◽

Satoshi Matsuzaki ◽

Jennifer R. Giorgione ◽

Kenneth M. Humphries

Keyword(s):

Insulin Signaling ◽

Phosphodiesterase Inhibitors ◽

Beta Agonist ◽

Diabetic Heart ◽

Dependent Manner ◽

Wild Type ◽

Independent Manner ◽

Primary Means ◽

Dependent Protein ◽

Underlying Mechanisms

AbstractThe cAMP-dependent protein kinase (PKA) signaling pathway is the primary means by which the heart regulates moment-to-moment changes in contractility and metabolism. We have previously found that PKA signaling is dysfunctional in the diabetic heart, yet the underlying mechanisms are not fully understood. The objective of this study was to determine if decreased insulin signaling contributes to a dysfunctional PKA response. To do so, we isolated adult cardiomyocytes (ACMs) from wild type and Akita type 1 diabetic mice. ACMs were cultured in the presence or absence of insulin and PKA signaling was visualized by immunofluorescence microscopy using an antibody that recognizes proteins specifically phosphorylated by PKA. We found significant decreases in proteins phosphorylated by PKA in wild type ACMs cultured in the absence of insulin. Akita ACMs also had decreased PKA signaling in the absence of insulin and this was not rescued by insulin. The decrease in PKA signaling was observed regardless of whether the kinase was stimulated with a beta-agonist, a cell-permeable cAMP analog, or with phosphodiesterase inhibitors. PKA content was unaffected, suggesting that the decrease in PKA signaling may be occurring by the loss of specific PKA substrates. Phospho-specific antibodies were therefore used to discern which potential substrates may be sensitive to the loss of insulin. Contractile proteins were phosphorylated similarly in wild type and Akita ACMs regardless of insulin. However, phosphorylation of the glycolytic regulator, PFK-2, was significantly decreased in an insulin-dependent manner in wild type ACMs and in an insulin-independent manner in Akita ACMs. These results demonstrate a defect in PKA activation in the diabetic heart, mediated in part by deficient insulin signaling, that results in an abnormal activation of a primary metabolic regulator.

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Selective Inhibition of Esophageal Cancer Stem-like Cells with Salinomycin

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200310093125 ◽

2020 ◽

Vol 20 (7) ◽

pp. 783-789

Author(s):

Mahdi Zarei ◽

Marie S. Jazi ◽

Mahboubeh Tajaldini ◽

Ayyoob Khosravi ◽

Jahanbakhsh Asadi

Keyword(s):

Gene Expression ◽

Esophageal Cancer ◽

Cancer Progression ◽

Cancer Cell Line ◽

Selective Inhibition ◽

P Value ◽

Xtt Assay ◽

Independent Manner ◽

Differential Toxicity ◽

Sphere Formation

Background: Targeting Cancer Stem-Like Cells (CSLCs) can provide promising new therapeutic strategies to inhibit cancer progression, metastasis and recurrence. Salinomycin (Sal), an antibacterial ionophore, has been shown to inhibit CSCs specifically. Recently, it has been reported that Sal can destabilize TAZ, the hypo pathway transducer in CSLCs. Objective: Here, in the current study, we aimed to assess the differential toxicity of Sal in esophageal CSLCs and its relation to TAZ gene expression. Methods: The esophageal cancer cell line, KYSE-30, was used for the enrichment of CSLCs. The expression of TAZ was knocked down using specific siRNA transfection and then the cytotoxicity of Sal was measured using XTT assay. The qRT-PCR method was used for gene expression assessment and the sphere formation ability was monitored using light microscopy. Result: Our findings showed that esophageal CSLCs over-express stemness-associated genes, including SOX2, OCT4 as well as TAZ (~14 fold, P value=0.02) transcription coactivator. We found Sal can selectively inhibit KYSE-30 CSLCs viability and sphere formation ability; however, TAZ knockdown does not change its differential toxicity. Conclusion: Overall, our results indicated that Sal can selectively decrease the viability of esophageal CSLCs in a TAZ-independent manner.

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FGFs and BMP4 induce both Msx1-independent and Msx1-dependent signaling pathways in early tooth development

Development ◽

10.1242/dev.125.21.4325 ◽

1998 ◽

Vol 125 (21) ◽

pp. 4325-4333 ◽

Cited By ~ 13

Author(s):

M. Bei ◽

R. Maas

Keyword(s):

Signaling Pathways ◽

Tooth Development ◽

Signaling Molecules ◽

Dependent Manner ◽

Wild Type ◽

Independent Manner ◽

Dental Lamina ◽

Bmp4 Expression ◽

Dental Epithelium ◽

Tooth Germs

During early tooth development, multiple signaling molecules are expressed in the dental lamina epithelium and induce the dental mesenchyme. One signal, BMP4, has been shown to induce morphologic changes in dental mesenchyme and mesenchymal gene expression via Msx1, but BMP4 cannot substitute for all the inductive functions of the dental epithelium. To investigate the role of FGFs during early tooth development, we examined the expression of epithelial and mesenchymal Fgfs in wild-type and Msx1 mutant tooth germs and tested the ability of FGFs to induce Fgf3 and Bmp4 expression in wild-type and Msx1 mutant dental mesenchymal explants. Fgf8 expression is preserved in Msx1 mutant epithelium while that of Fgf3 is not detected in Msx1 mutant dental mesenchyme. Moreover, dental epithelium as well as beads soaked in FGF1, FGF2 or FGF8 induce Fgf3 expression in dental mesenchyme in an Msx1-dependent manner. These results indicate that, like BMP4, FGF8 constitutes an epithelial inductive signal capable of inducing the expression of downstream signaling molecules in dental mesenchyme via Msx1. However, the BMP4 and FGF8 signaling pathways are distinct. BMP4 cannot induce Fgf3 nor can FGFs induce Bmp4 expression in dental mesenchyme, even though both signaling molecules can induce Msx1 and Msx1 is necessary for Fgf3 and Bmp4 expression in dental mesenchyme. In addition, we have investigated the effects of FGFs and BMP4 on the distal-less homeobox genes Dlx1 and Dlx2 and we have clarified the relationship between Msx and Dlx gene function in the developing tooth. Dlx1,Dlx2 double mutants exhibit a lamina stage arrest in maxillary molar tooth development (Thomas B. L., Tucker A. S., Qiu M., Ferguson C. A., Hardcastle Z., Rubenstein J. L. R. and Sharpe P. T. (1997) Development 124, 4811–4818). Although the maintenance of molar mesenchymal Dlx2 expression at the bud stage is Msx1-dependent, both the maintenance of Dlx1 expression and the initial activation of mesenchymal Dlx1 and Dlx2 expression during the lamina stage are not. Moreover, in contrast to the tooth bud stage arrest observed in Msx1 mutants, Msx1,Msx2 double mutants exhibit an earlier phenotype closely resembling the lamina stage arrest observed in Dlx1,Dlx2 double mutants. These results are consistent with functional redundancy between Msx1 and Msx2 in dental mesenchyme and support a model whereby Msx and Dlx genes function in parallel within the dental mesenchyme during tooth initiation. Indeed, as predicted by such a model, BMP4 and FGF8, epithelial signals that induce differential Msx1 and Msx2 expression in dental mesenchyme, also differentially induce Dlx1 and Dlx2 expression, and do so in an Msx1-independent manner. These results integrate Dlx1, Dlx2 and Fgf3 and Fgf8 into the odontogenic regulatory hierarchy along with Msx1, Msx2 and Bmp4, and provide a basis for interpreting tooth induction in terms of transcription factors which, individually, are necessary but not sufficient for the expression of downstream signals and therefore must act in specific combinations.

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Analysis of the Manganese and MntR Regulon in Corynebacterium diphtheriae

Journal of Bacteriology ◽

10.1128/jb.00274-21 ◽

2021 ◽

Author(s):

Eric D. Peng ◽

Lindsey R. Lyman ◽

Michael P. Schmitt

Keyword(s):

Gene Expression ◽

Dna Binding ◽

Pathogenic Bacteria ◽

Expression Profiles ◽

Cadmium Toxicity ◽

Corynebacterium Diphtheriae ◽

Uptake System ◽

Dependent Manner ◽

Wild Type ◽

Binding Studies

Corynebacterium diphtheriae is the causative agent of a severe respiratory disease in humans. The bacterial systems required for infection are poorly understood, but the acquisition of metals such as manganese (Mn) is likely critical for host colonization. MntR is a Mn-dependent transcriptional regulator in C. diphtheriae that represses the expression of the mntABCD genes, which encode a putative ABC metal transporter. However, other targets of Mn and MntR regulation in C. diphtheriae have not been identified. In this study, we use comparisons between the gene expression profiles of wild-type C. diphtheriae strain 1737 grown without or with Mn supplementation and comparisons of gene expression between wild-type and an mntR deletion mutant to characterize the C. diphtheriae Mn and MntR regulon. MntR was observed to both repress and induce various target genes in a Mn-dependent manner. Genes induced by MntR include the Mn-superoxide dismutase, sodA , and the putative ABC transporter locus, iutABCD . DNA binding studies showed that MntR interacts with the promoter regions for several genes identified in the expression study, and a 17-bp consensus MntR DNA binding site was identified. We found that an mntR mutant displayed increased sensitivity to Mn and cadmium that could be alleviated by the additional deletion of the mntABCD transport locus, providing evidence that the MntABCD transporter functions as a Mn uptake system in C. diphtheriae . The findings in this study further our understanding of metal uptake systems and global metal regulatory networks in this important human pathogen. Importance Mechanisms for metal scavenging are critical to the survival and success of bacterial pathogens, including Corynebacterium diphtheriae . Metal import systems in pathogenic bacteria have been studied as possible vaccine components due to high conservation, critical functionality, and surface localization. In this study, we expand our understanding of the genes controlled by the global manganese regulator, MntR. We determined a role for the MntABCD transporter in manganese import using evidence from manganese and cadmium toxicity assays. Understanding the nutritional requirements of C. diphtheriae and the tools used to acquire essential metals will aid in the development of future vaccines.

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HIF-2α regulates murine hematopoietic development in an erythropoietin-dependent manner

Blood ◽

10.1182/blood-2004-05-1695 ◽

2005 ◽

Vol 105 (8) ◽

pp. 3133-3140 ◽

Cited By ~ 139

Author(s):

Marzia Scortegagna ◽

Kan Ding ◽

Quiyang Zhang ◽

Yavuz Oktay ◽

Michael J. Bennett ◽

...

Keyword(s):

Gene Expression ◽

Hypoxia Inducible Factor ◽

Regulatory Region ◽

Dependent Manner ◽

Wild Type ◽

Hematopoietic Development ◽

Erythropoietin Production ◽

Hypoxia Treatment

AbstractErythropoiesis in the adult mammal depends critically on erythropoietin, an inducible cytokine with pluripotent effects. Erythropoietin gene expression increases under conditions associated with lowered oxygen content such as anemia and hypoxia. HIF-1α, the founding member of the hypoxia-inducible factor (HIF) alpha class, was identified by its ability to bind and activate the hypoxia-responsive enhancer in the erythropoietin regulatory region in vitro. The existence of multiple HIF alpha members raises the question of which HIF alpha member or members regulates erythropoietin expression in vivo. We previously reported that mice lacking wild-type HIF-2α, encoded by the EPAS1 gene, exhibit pancytopenia. In this study, we have characterized the etiology of this hematopoietic phenotype. Molecular studies of EPAS1-null kidneys reveal dramatically decreased erythropoietin gene expression. EPAS1-null as well as heterozygous mice have impaired renal erythropoietin induction in response to hypoxia. Treatment of EPAS1-null mice with exogenous erythropoietin reverses the hematopoietic and other defects. We propose that HIF-2α is an essential regulator of murine erythropoietin production. Impairments in HIF signaling, involving either HIF-1α or HIF-2α, may play a prominent role in conditions involving altered hematopoietic or erythropoietin homeostasis.

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C-reactive protein inhibits adiponectin gene expression and secretion in 3T3-L1 adipocytes

Journal of Endocrinology ◽

10.1677/joe-07-0133 ◽

2007 ◽

Vol 194 (2) ◽

pp. 275-281 ◽

Cited By ~ 32

Author(s):

Guoyue Yuan ◽

Xia Chen ◽

Qinyun Ma ◽

Jie Qiao ◽

Rongying Li ◽

...

Keyword(s):

Gene Expression ◽

Gene Promoter ◽

Luciferase Reporter ◽

Dependent Manner ◽

Adiponectin Gene ◽

C Reactive Protein ◽

Reactive Protein ◽

Markers Of Inflammation ◽

Adiponectin Mrna ◽

Reporter Assays

C-reactive protein (CRP) is considered as one of the most sensitive markers of inflammation. The aim of the present study is to investigate the effects of CRP on the production of adiponectin in 3T3-L1 adipocytes. Northern and western blot analysis revealed that CRP treatment inhibited adiponectin mRNA expression and secretion in a dose- and time-dependent manner. Co-incubation of adipocytes with rosiglitazone and CRP decreased induction of adiponectin gene expression by rosiglitazone. However, luciferase reporter assays did not show that CRP affected the activity of ~2.1 kb adiponectin gene promoter, which was increased by rosiglitazone alone. Pharmacological inhibition of phosphatidylinositol (PI)-3 kinase by LY294002 partially reversed inhibition of adiponectin gene expression by CRP. These results collectively suggest that CRP suppresses adiponectin gene expression partially through the PI-3 kinase pathway, and that decreased production of adiponectin might represent a mechanism by which CRP regulates insulin sensitivity.

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