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Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach.

ABSTRACT: Reversibility of hepatic fibrosis is an intrinsic response to chronic injury, and with on-going damage, fibrosis can progress to its end-stage consequence, cirrhosis. Non-invasive and reliable biomarkers for early detection of liver fibrosis are needed. Based on the CCl4-induced liver fibrosis rat model, urinary and serum metabolic profiling performed by LC-QTOF-MS associated with histological progression were utilized to identify liver fibrosis-specific potential biomarkers for early prediction and to reveal significant fibrotic pathways and their dynamic changes in different stages of liver fibrosis. Finally, nine differential metabolites in urine and ten in serum were selected and identified involving the most relevant metabolic pathways. Perturbations of tryptophan, valine, leucine, isoleucine, and citrate (TCA) cycle metabolites, along with sphingolipid and glycerophospholipid metabolites, occurred from the onset of liver fibrosis. Furthermore, dysregulation of valine and bile acid biosynthesis metabolites occurred in the intermediate and advanced stages. More importantly, among these metabolites, urinary kynurenic acid, 5-hydroxyindoleacetyl glycine, 4-(2-amino-3-hydroxyphenyl)-2,4-dioxobutanoic acid and serum sphinganine, sphingomyelin,? L-leucine, L-tryptophan, and LysoPC(17:0) changed at all time points and may serve as potential early biomarkers for the diagnosis of hepatic fibrosis and as therapeutic targets. Overall, this work evaluates the potential of these metabolites for the early detection of liver fibrosis.

SUBMITTER: Chang H

PROVIDER: S-EPMC5595818 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach.

Chang Hong H Meng Hong-Yu HY Liu Shu-Min SM Wang Yu Y Yang Xiao-Xu XX Lu Fang F Wang Hong-Yu HY

Scientific reports 20170912 1

Reversibility of hepatic fibrosis is an intrinsic response to chronic injury, and with on-going damage, fibrosis can progress to its end-stage consequence, cirrhosis. Non-invasive and reliable biomarkers for early detection of liver fibrosis are needed. Based on the CCl<sub>4</sub>-induced liver fibrosis rat model, urinary and serum metabolic profiling performed by LC-QTOF-MS associated with histological progression were utilized to identify liver fibrosis-specific potential biomarkers for early ...[more]

PMID: 28900168

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Project description:Liver fibrosis is caused by liver injury induced by a number of chronic liver diseases, including schistosome infection, hepatitis infection, metabolic disease, alcoholism and cholestasis. The tissue damage occurring after injury or inflammation of the liver is a reversible lesion; however, liver fibrosis has become a worldwide problem and poses a threat to human health. The development of an effective drug for the prevention and treatment of liver fibrosis is ongoing and uses information from different occurrences of liver fibrosis. In the present study, carbon tetrachloride (CCl4)-induced metabonomic changes in serum and urine at 12 weeks were analyzed using gas chromatography-mass spectrometry (GC/MS) to investigate potential biomarkers. Liver fibrosis was induced in rats by subcutaneous injections of CCl4 twice a week for 12 consecutive weeks. Histopathological changes were used to assess the successful production of a CCl4-induced liver fibrosis model. Serum and urine samples from the two groups were collected at 12 weeks. The metabolic profile changes were analyzed by GC/MS alongside principal component analysis and orthogonal projections to latent structures. Metabolic profile studies indicated that the clustering of the two groups could be separated and seven metabolites in serum and five metabolites in urine were identified. In serum, the metabolites identified included isoleucine, L-malic acid, α-copper, carnitine, hippuric acid, glutaric acid and glucose. In urine 2-hydroxy butyric acid, isoleucine, N-acetyl-β-alanine, cytidine and corticoid were identified. The present study demonstrated that the pathogenesis of liver fibrosis may be associated with the dysfunction of a number of metabolic pathways, including glucose, amino acid, P450, fatty acid, nucleic acid, water-electrolyte and glutathione biosynthesis. Assessing potential biomarkers may therefore provide novel targets and theories for the innovation of novel drugs to prevent and cure liver fibrosis.

Project description:IntroductionIndividuals with metabolic syndrome (MetS) are at increasing risk of coronary artery disease (CAD). We investigated the common metabolic perturbations of CAD and MetS via serum metabolomics to provide insight into potential associations.MethodsNon-targeted serum metabolomics analyses were performed using ultra high-performance liquid chromatography coupled with Q Exactive hybrid quadrupole-orbitrap high-resolution accurate mass spectrometry (UHPLC-Q-Orbitrap HRMS) in samples from 492 participants (272 CAD vs. 121 healthy controls (HCs) as cohort 1, 55 MetS vs. 44 HCs as cohort 2). Cross-sectional data were obtained when the participants were recruited from the First Affiliated Hospital of Zhengzhou University. Multivariate statistics and Student's t test were applied to obtain the significant metabolites [with variable importance in the projection (VIP) values >1.0 and p values <0.05] for CAD and MetS. Logistic regression was performed to investigate the association of identified metabolites with clinical cardiac risk factors, and the association of significant metabolic perturbations between CAD and MetS was visualized by Cytoscape software 3.6.1. Finally, the receiver operating characteristic (ROC) analysis was evaluated for the risk prediction values of common changed metabolites.ResultsThirty metabolites were identified for CAD, mainly including amino acids, lipid, fatty acids, pseudouridine, niacinamide; 26 metabolites were identified for MetS, mainly including amino acids, lipid, fatty acids, steroid hormone, and paraxanthine. The logistic regression results showed that all of the 30 metabolites for CAD, and 15 metabolites for MetS remained significant after adjustments of clinical risk factors. In the common metabolic signature association analysis between CAD and MetS, 11 serum metabolites were significant and common to CAD and MetS outcomes. Out of this, nine followed similar trends while two had differing directionalities. The nine common metabolites exhibiting same change trend improved risk prediction for CAD (86.4%) and MetS (90.9%) using the ROC analysis.ConclusionSerum metabolomics analysis might provide a new insight into the potential mechanisms underlying the common metabolic perturbations of CAD and MetS.

Project description:BackgroundRhein can significantly delay the progression of chronic nephropathy. However, its mechanism of action has not been adequately elaborated, which hinders its extensive clinical application. In this work, the effects of rhein on models of TGF-β-induced NRK-49F cellular fibrosis and rat renal ischemia-reperfusion fibrosis were evaluated using metabolomics and western blotting.MethodsThe metabolic profiles of NRK-49F cells and rat urine, serum, and kidney tissues in the control, model, and rhein groups were investigated using UPLC-QTOF-MS. The levels of p-P65, p-IKK, p-AKT, p-P38, p-JNK and AP-1 in NRK-49F cells were measured using western blotting and immunofluorescence methods. Molecular docking and network pharmacology methods were employed to explore the relationship between the potential targets of rhein and key proteins in the NF-κB and MAPK signaling pathways.ResultsVarious potential metabolites, including sphingolipids, ceramides, phosphatidylcholine, and lysophosphatidylcholine,14-hydroxy-E4-neuroprostane E, and 5-HPETE, were present in the cell, tissue, urine, and serum samples; however, few metabolites matches exactly among the four type of biological samples. These differential metabolites can effectively differentiated between the control, model, and rhein groups. Pathway enrichment analysis of differential metabolites unveiled that sphingolipid metabolism, arachidonic acid metabolism, and glycerophospholipid metabolism were closely related to nephropathy. Phosphorylation levels of AKT, IKK, P65 and AP-1 in NRK-49F cells was reduced by rhein treatment. Network pharmacology and molecular docking showed that the potential targets of rhein might regulated the expression of MAPK and AKT in the NF-κB and MAPK signaling pathways.ConclusionIn brief, rhein might delays the progression of chronic nephropathy via the metabolic pathways, NF-κB and MAPKs signaling pathways, which provides the foundation for its development and clinical application.

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Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach.

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Identification of key metabolic changes during liver fibrosis progression in rats using a urine and serum metabolomics approach.

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