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. 2017 Mar 14;12(3):e0173598.
doi: 10.1371/journal.pone.0173598. eCollection 2017.

Metabolomic Mechanisms of Gypenoside Against Liver Fibrosis in Rats: An Integrative Analysis of Proteomics and Metabolomics Data

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Free PMC article

Metabolomic Mechanisms of Gypenoside Against Liver Fibrosis in Rats: An Integrative Analysis of Proteomics and Metabolomics Data

Ya-Nan Song et al. PLoS One. .
Free PMC article

Abstract

Aims: To investigate mechanisms and altered pathways of gypenoside against carbon tetrachloride (CCl4)-induced liver fibrosis based on integrative analysis of proteomics and metabolomics data.

Methods: CCl4-induced liver fibrosis rats were administrated gypenoside. The anti-fibrosis effects were evaluated by histomorphology and liver hydroxyproline (Hyp) content. Protein profiling and metabolite profiling of rats liver tissues were examined by isobaric tags for relative and absolute quantitation (iTRAQ) approach and gas chromatography-mass spectrometer (GC-MS) technology. Altered pathways and pivotal proteins and metabolites were searched by integrative analysis of proteomics and metabolomics data. The levels of some key proteins in altered pathways were determined by western blot.

Results: Histopathological changes and Hyp content in gypenoside group had significant improvements (P<0.05). Compared to liver fibrosis model group, we found 301 up-regulated and 296 down-regulated proteins, and 9 up-regulated and 8 down-regulated metabolites in gypenoside group. According to integrative analysis, some important pathways were found, including glycolysis or gluconeogenesis, fructose and mannose metabolism, glycine, serine and threonine metabolism, lysine degradation, arginine and proline metabolism, glutathione metabolism, and sulfur metabolism. Furthermore, the levels of ALDH1B1, ALDH2 and ALDH7A1 were found increased and restored to normal levels after gypenoside treated (P<0.05).

Conclusions: Gypenoside inhibited CCl4-induced liver fibrosis, which may be involved in the alteration of glycolysis metabolism and the protection against the damage of aldehydes and lipid peroxidation by up-regulating ALDH.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Effects of gypenoside on histological changes of liver fibrosis rats.
(A) H&E staining (*200) and Sirius red staining (*100). (B) Hyp content. (C: control group; M: liver fibrosis model group; G: gypenoside group. Data are shown as mean ± SD. ### P<0.001 (vs. Control); * P<0.05 (vs. Model).)
Fig 2
Fig 2. Proteomics analysis of gypenoside-treated liver fibrosis rats.
(A) Heatmap of the significantly altered proteins in control, model and gypenoside group. Red represents an up-regulation, and green represents a down-regulation in protein expression. The proteins were clustered into four broad clusters. (B) Representative Gene Ontology (GO) biological processes (P<0.001) of differentially expressed proteins between gypenoside and model groups. (C) Log-log plot of the two conditions M/C and G/M based on protein expression ratios. Outstanding protein expression changes are indicated according to their gene names. (C: control group; M: liver fibrosis model group; G: gypenoside group.)
Fig 3
Fig 3. Metabolomics analysis of gypenoside-treated liver fibrosis rats.
(A) Score plots of PCA analysis of control group, model group and gypenoside group. (B) Log-log plot of the two conditions M/C and G/M based on metabolite expression ratios. Outstanding metabolite expression changes are indicated according to their names, and other unlabeled outstanding metabolites were not identified. (C: control group; M: liver fibrosis model group; G: gypenoside group.)
Fig 4
Fig 4. The networks of significantly altered metabolic pathways in response to gypenoside.
Pathways are showed in yellow dashed areas. Proteins are showed in rectangles, and metabolites are showed in no rectangles. Red represents up-regulation in gypenoside group compared to model group, and blue represents down-regulation.
Fig 5
Fig 5. Effect of gypenoside on hepatic protein levels.
Hepatic protein levels of ALDH1B1, ALDH2 and ALDH7A1 were examined in control, model and gypenoside groups by western blot. Hepatic GAPDH level was used as loading control. (C: control group; M: liver fibrosis model group; G: gypenoside group. Data are shown as mean ± SD. # P<0.05, ## P<0.01 (vs. Control); * P<0.05, ** P<0.01 (vs. Model).)

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Grant support

This work was supported by Key Program of National Natural Science Foundation of China (81330084), National Science and Technology Major Project of China (2009ZX09311-003), and E-institutes of Shanghai Municipal Education Commission (E03008).
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