Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Novel Role in Autophagy

ABSTRACT: This SuperSeries is composed of the following subset Series: GSE28082: Examination of hepatic SREBP-2 binding using ChIP-Seq GSE28083: Expression data from CH/LE Mice Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Jacob Biesinger

PROVIDER: E-GEOD-28084 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy.

Seo Young-Kyo YK Jeon Tae-Il TI Chong Hansook Kim HK Biesinger Jacob J Xie Xiaohui X Osborne Timothy F TF

Cell metabolism 20110401 4

Sterol regulatory element-binding proteins (SREBPs) are key transcriptional regulators of lipid metabolism. To define functional differences between the three mammalian SREBPs we used genome-wide ChIP-seq with isoform-specific antibodies and chromatin from select tissues of mice challenged with different dietary conditions that enrich for specific SREBPs. We show that hepatic SREBP-2 binds preferentially to two different gene-proximal motifs. A Gene Ontology (GO) analysis suggests SREBP-2 target ...[more]

PMID: 21459322

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Project description:Background: Genetic elimination of c-Met signaling in the liver has been shown to impact many cellular pathways involved in repair, regeneration, lipid homeostasis and redox balance. In this study, we analyzed a nutritional model of hepatic steatosis in Met fl/fl ; Alb-Cre +/- (MetKO) mice in a 129SV/C57BL/6 background fed a high cholesterol diet for 30 days. Methods: Liver injury was determined by histopathology and plasma enzymes, transcriptomic changes were examined using gene expression microarrays, and evaluation of key molecules involved in liver damage and lipid homestasis were evaluated by Western blot analysis. Results: We observed that in comparison with wild type mice subjected to the same diet, MetKO mice developed a strong liver lipid deposition, inflammatory infiltration and increment in total bile acids synthesis and liver damage markers. Global transcriptomic changes analysis confirmed the steatosis and cholestasis induced by the high cholesterol diet. In addition, we found affected pathways related to amino acids, glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction. Oxidative stress exacerbation was corroborated by lipid and protein oxidation in liver tissue. To address further, Western blot studies revealed downregulation on Erk, NF-kB and Nrf2 survival pathways and target genes (cyclin D1, SOD1, gamma-GCS), an increment in proapoptotic proteins (p53, caspase 3) and changes in nuclear receptors such as RAR and RXR, which were increased, and CAR, FXR and PPAR alfa, which were decreased, in the MetKO diet. These results are in agreement with the steatosis and cholestasis phenotype. Conclusion: Our data provide evidence of c-Met signaling involvement in lipid metabolism, and bile acids synthesis and excretion. Disruption of these pathways leads to liver dysfunction, improper metabolism and hepatocellular damage. Global transcriptome changes between WT mice vs. c-Met KO mice fed a 2% cholesterol and 0.5% sodium cholate diet (high cholesterol) or a Chow regular diet (Chow) as control. Mice were fed a high cholesterol or chow regular diet for 30 days. Liver tissue was obtained, and RNA was extracted and subjected to Illumina microarray analysis.

Dataset Information

Genome-wide Localization of SREBP-2 in Hepatic Chromatin Predicts a Novel Role in Autophagy

Publications

Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy.

Similar Datasets

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