Project description:Gene expression: Identification of primary target genes of liver X receptor (LXR) in an immune-related cellular model (THP-1 cells) to study, in conjunction with LXR binding data from ChIP-seq, the genome-wide mechanisms of transcriptional regulation by LXR. ChIP-Seq: We performed ChIP-seq in macrophage-type PMA-differentiated THP-1 cells after stimulation with the potent synthetic LXR ligand T0901317 (T09). As a reference we performed microarray gene expression analysis in the same cellular model. We identified in total 1357 LXR binding locations on chromatin (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR site sequences identified DR4-type binding sites as major motif. gene expression: THP-1 cells were treated for 4 h with 1 M-BM-5M T09 or vehicle (DMSO) ChIP-Seq: PMA-differentiated THP-1 cells were treated for 60 min with 1 M-BM-5M T09 or vehicle (DMSO)
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.
Project description:RNA samples from brain, cerebellum, liver, and testis of 3-year-old make Macaca fascicularis was hybridized to the M.fascicularis GeneChip, which was designed by the Laboratory of Genetic Resources, National Institute of Biomedical Innovation. Keywords: Control study
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.
Project description:In order to develop new safe and potent therapeutics, insights into the mechanisms underlying diabetes mellitus are urgently needed. We used proteomics profiling of the liver tissue from Macaca fascicularis with spontaneously occurred diabetes mellitus at their middle age and including two groups of the monkeys fed with the same food and high-fat and high-sugar diet for comparison.We hoped to find something new for diabetes mellitus treatment.
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
Project description:Liver gene expression was examined in male cynomolgus monkeys treated with ciprofibrate (PPAR-alpha agonist) for 4 days at 400 mg/kg/day and treated for 15 days at 0, 3, 30, 150 or 400 mg/kg/day. The untreated control group were given only the vehicle (0.5% hydroxypropyl methylcellulose). Two animals per group were used for the 4 day treatment and four animals per group were used for the 15 day treatment (except the 15 day control group, which had three animals). Selection of significantly changed probesets was done using Rosetta Resolver and the fold-change and p values as determined by Resolver are given below. Affymetrix CEL files and MAS5-processed data have been made availabe for convenience. Note that data processing reported in the Toxicological Sciences manuscript was done using Rosetta Resolver and the treated versus control group fold-change and p-value are appended to the Series entry. An article has been published in Toxicological Sciences regarding this dataset; the data interpretation was based on the Rosetta Resolver data. Experiment Overall Design: Groups consisted of (i) vehicle only for 4 days, (ii) 400 mg/kg/day ciprofibrate for 4 days, (iii) vehicle only for 15 days and (iv) 3, 30, 150, or 400 mg/kg/day ciprofibrate for 15 days.