Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Effect of dietary cholesterol on gene expression in the liver of apoE-KO mice

ABSTRACT: Apolipoprotein E-knock out (apoE-KO) mouse is known as a model animal for atherosclerosis accompanied by spontaneous hypercholesterolemia. When apoE-KO mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet), cholesterol and bile acids were highly increased in the liver within a week. However, the amount of triacylglycerol (TG) in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost diminished in the long term. Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of TG synthesis remains to be elucidated. To evaluate the impact of high-Chol diet for 1 week on gene expression in the liver of apoE-KO mice, DNA microarray analysis was performed with comparison to apoE-KO mice fed a normal chow. We found that mRNA expression related to lipid metabolism was suppressed by the high-Chol diet in the liver of apoE-KO mice, which includes beta-oxidation and glycerol-3-phosphate (G3P) pathway for TG synthesis. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased. PGC-1?, which up-regulates the transcription of lipin-1, was also suppressed. Lipin is reported to function as a coactivator of PGC-1? and is an inducible amplifier of PPAR?, indicating that the suppression of genes involved in beta-oxidation could be induced by suppression of the lipins. These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver. Apo E-KO mice at 10 weeks of age were fed normal chow (control) or high-Chol diet containing 1.25% cholesterol for 1 week. Three independent experiments were performed at each diet.

ORGANISM(S): Mus musculus

SUBMITTER: Takashi Obama

PROVIDER: E-GEOD-27457 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

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Effect of dietary cholesterol on gene expression in the liver of apoE-KO mice

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