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| Status |
Public on Jul 11, 2012 |
| Title |
Conditional elimination of c-Met signaling in the liver aggravates oxidative stress and cholestasis, and deregulates lipid metabolism, under a high cholesterol diet |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Gomez-Quiroz LE, Seo D, Gillen M, Thorgeirsson SS |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Jul 13, 2011 |
| Last update date |
Jun 14, 2018 |
| Contact name |
Daekwan Seo |
| E-mail(s) |
daekwan_seo@nih.gov
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| Phone |
301-496-5688
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| Fax |
301-496-0734
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| Organization name |
NIH
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| Department |
NCI
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| Lab |
LEC
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| Street address |
37 Convent Dr. Rm 4140
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20878 |
| Country |
USA |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (16)
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| GSM759952 |
Chow Diet, WT mice, rep4 |
| GSM759953 |
Chow Diet, c-Met KO mice, rep1 |
| GSM759954 |
Chow Diet, c-Met KO mice, rep2 |
| GSM759955 |
Chow Diet, c-Met KO mice, rep3 |
| GSM759956 |
Chow Diet, c-Met KO mice, rep4 |
| GSM759957 |
High Cholesterol Diet, WT mice, rep1 |
| GSM759958 |
High Cholesterol Diet, WT mice, rep2 |
| GSM759959 |
High Cholesterol Diet, WT mice, rep3 |
| GSM759960 |
High Cholesterol Diet, WT mice, rep4 |
| GSM759961 |
High Cholesterol Diet, c-Met KO mice, rep1 |
| GSM759962 |
High Cholesterol Diet, c-Met KO mice, rep2 |
| GSM759963 |
High Cholesterol Diet, c-Met KO mice, rep3 |
| GSM759964 |
High Cholesterol Diet, c-Met KO mice, rep4 |
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| Relations |
| BioProject |
PRJNA144613 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE30651_RAW.tar |
3.1 Mb |
(http)(custom) |
TAR |
| GSE30651_non-normalized.txt.gz |
2.8 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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