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Transcription profiling of livers from Low Density Lipoprotein Receptor null mice expressing human LXR alpha to explore the molecular basis of metabolic effects of increased hepatic hLXR alpha.

ABSTRACT: Microarray analysis of liver RNA from male Low Density Lipoprotein Receptor null mice on C57B6 background expressing human LXR alpha or GFP (control) via adeno-associated virus (AAV2.8) gene transfer, under control of the liver specific human thyroxine binding globulin promoter. Samples are from 8 month old mice, with AAV treatment at age of 10 weeks, on Western diet for 12 weeks prior experiment. The synthetic LXR ligand T0901317 (5mg/kg) or vehicle was administered for 3 days by i.p. injection to designated mice.

ORGANISM(S): Mus musculus

SUBMITTER: Mitchell Lazar

PROVIDER: E-GEOD-2644 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRalpha.

Lehrke Michael M Lebherz Corinna C Millington Segan C SC Guan Hong-Ping HP Millar John J Rader Daniel J DJ Wilson James M JM Lazar Mitchell A MA

Cell metabolism 20050501 5

The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. Liver X receptors (LXRs) are oxysterol sensors that are required for normal cholesterol and triglyceride homeostasis, yet synthetic LXR agonists produce undesirable hypertriglyceridemia. Here we report a previously unrecognized role for hepatic LXRalpha in the links between diet, serum lipids, and atherosclerosis. A modest increase in ...[more]

PMID: 16054077

Similar Datasets

Diet-dependent cardiovascular lipid metabolism controlled by hepatic LXRα

Project description:Microarray analysis of liver RNA from male Low Density Lipoprotein Receptor null mice on C57B6 background expressing human LXR alpha or GFP (control) via adeno-associated virus (AAV2.8) gene transfer, under control of the liver specific human thyroxine binding globulin promoter. Samples are from 8 month old mice, with AAV treatment at age of 10 weeks, on Western diet for 12 weeks prior experiment. The synthetic LXR ligand T0901317 (5mg/kg) or vehicle was administered for 3 days by i.p. injection to designated mice. Keywords = LXR alpha Keywords = SREBP1 Keywords = diet Keywords = lipid metabolism Keywords = atherosclerosis Keywords: repeat sample

2005-05-12 | GSE2644 | GEO

Impact of LXR activation on alternatively activated human macrophages

Project description:To investigate how LXR activation potentiates expression of Th2 cytokine-dependent genes in primary human macrophages, we pulsed macrophages with synthetic LXR ligand T0901317 then polarized cells to alternatively activated macrophages with IL-4 or IL-13.

2021-04-14 | GSE158022 | GEO

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRM-NM-1 and LXRM-NM-2 subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRM-NM-1 and LXRM-NM-2 knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRM-NM-1 KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRM-NM-2 KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRM-NM-1 KO mice, but not LXRM-NM-2 KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRM-NM-2 in skeletal muscle. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRa and LXRb knockout (KO) mice were established. Sixteen samples were examined. Half the samples were treated with the unselective LXR agonist T0901317.

2010-03-30 | E-GEOD-13192 | biostudies-arrayexpress

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRα and LXRβ subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRα and LXRβ knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRα KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRβ KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRα KO mice, but not LXRβ KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRβ in skeletal muscle.

2010-03-31 | GSE13192 | GEO

Transcription profiling of mouse LXRalpha null, LXRbeta null mutants reveals liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRalpha (NR1H3) and LXRbeta (NR1H2) subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRalpha and LXRbeta knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRalpha KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRbeta KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRalpha KO mice, but not LXRbeta KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRbeta in skeletal muscle.

2009-10-01 | E-MTAB-61 | biostudies-arrayexpress

Genome-wide profiling of LXR, RXR and PPARM-NM-1 in mouse liver reveals extensive sharing of binding sites

Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARM-NM-1 binding demonstrated binding of PPARM-NM-1 to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARM-NM-1:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARM-NM-1 at the level of binding to shared genomic sites LXR, RXR, PPARalpha and RNA Polymerase II ChIP-seq on livers from female C57BL/6 wild-type and/or LXRM-NM-1/M-NM-2-deficient mice (13 weeks of age, n=1) treated by oral gavage once daily for 14 days with the RXR agonist bexarotene (100 mg/kg body weight [mpk], in 1% carboxymethylcellulose), the LXR agonist T0901317 (T09, 30 mpk) or vehicle alone.

2012-01-31 | E-GEOD-35262 | biostudies-arrayexpress

Effects of LXR activation in zebrafish larvae

Project description:The Liver X Receptors (LXRs) play important roles in multiple metabolic pathways, including fatty acid, cholesterol, carbohydrate and energy metabolism. To expand the knowledge of the functions of LXR signaling during embryonic development, we performed a whole-genome microarray analysis of Lxr target genes in zebrafish larvae treated with either one of the synthetic LXR ligands T0901317 or GW3965. Assessment of the biological processes enriched by differentially expressed genes revealed a prime role for Lxr in regulating lipid metabolic processes, similarly to the function of LXR in mammals. In addition, exposure to the Lxr ligands induced changes in expression of genes in the neural retina and lens of the zebrafish eye, including the photoreceptor guanylate cyclase activators and lens gamma crystallins, suggesting a potential novel role for Lxr in modulating the transcription of genes associated with visual function in zebrafish. The regulation of expression of metabolic genes was phenotypically reflected in an increased absorption of yolk in the zebrafish larvae, and changes in the expression of genes involved in visual perception were associated with morphological alterations in the retina and lens of the developing zebrafish eye. The regulation of expression of both lipid metabolic and eye specific genes was sustained in 1 month old fish. The transcriptional networks demonstrated several conserved effects of LXR activation between zebrafish and mammals, and also identified potential novel functions of Lxr, supporting zebrafish as a promising model for investigating the role of Lxr during development.

2016-03-07 | GSE59031 | GEO

LXR mediated-signalling protects human hair follicles against doxorubicin-induced toxicity ex vivo

Project description:Although chemotherapy-induced alopecia (CIA) is one of the most distressing adverse effects of cancer treatment, there are still no pharmacological interventions available and there remains an urgent unmet need to identify novel targets for therapy. We hypothesized that selected compounds which enhance ABC transporter activity and thus drug efflux from CIA-affected hair follicle (HF) epithelium may award relative protection from chemotherapy-induced HF toxicity. We found that the LXR agonist T0901317 significantly increased cell survival, attenuated LDH release, caspase-3 activity and DNA double strand breaks (DSBs) in doxorubicin (DOX)-treated outer root sheath keratinocytes (ORS-KCs) in vitro and protected human HFs from DOX-induced apoptosis ex vivo. RNA sequencing was performed to investigate the potential mechanism(s) by which T0901317 may protect against DOX-induced cell survival and apoptosis of ORS-KC.

2021-02-19 | E-MTAB-9362 | biostudies-arrayexpress

Effect of LXR agonist T0901317 on the intestinal transcriptome in mice.

Project description:Mice were treated for three days by oral gavage with the synthetic LXR ligand T0901317 (Cayman chemical, USA) using a dose of 50 mg/kg/day in vehicle (0.5% Carboxy-methylcellulose; 400 cPs (Sigma-Aldrich, USA); 0.2% Tween80 (Sigma-Aldrich, USA)) or solely the vehicle (control group). Mice were anesthetized with isoflurane and euthanized by cardiac puncture followed by cervical dislocation. Intestines were flushed with ice cold PBS and frozen in liquid nitrogen.

2020-10-27 | GSE110528 | GEO

Genome-wide profiling of LXR, RXR and PPARα in mouse liver reveals extensive sharing of binding sites

Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARα binding demonstrated binding of PPARα to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARα:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARα at the level of binding to shared genomic sites

2012-01-31 | GSE35262 | GEO

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