Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Liver transcriptome profiles correlates with viral control during hepatitis B virus infection

ABSTRACT: The natural history of chronic hepatitis B virus (HBV) infection could be divided in different phases by transaminase and HBV replication levels. However, it remains unknown how the intrahepatic transcriptomes in patients are correlated with the clinical phases. Here, we determined the intrahepatic transcriptomes of chronic hepatitis B patients and examined the role of specific groups of genes, including immune-related genes, in the control of hepatitis B virus infection. The transcriptomes of 83 chronic hepatitis B patients (22 immune tolerant, 50 immune clearance, and 11 inactive carrier state) were analyzed by performing microarray analysis of liver biopsies.KEGG pathway analysis showed that immune response genes and interferon-stimulated genes were up-regulated in the immune clearance phase. Although immune tolerant patients and inactive state carriers had significantly different serum viral loads, the hepatic transcriptomes of the two groups were largely similar and only significantly differed in the expression of 109 genes (p < 0.01). Thus, we hypothesized that some of the 109 genes may be involved in HBV control and identified genes of interest by performing systematic screening using specific siRNAs. We showed that silencing candidate genes such as EVA1A resulted in significantly increased viral replication. Conversely, overexpression of candidate genes suppressed virus replication. Conclusions: The immune related pathways were up-regulated in the immune clearance phase but not in the inactive carrier phase. A number of host genes unrelated to immune pathways were expressed in the inactive carrier phase and these may participate in the control of hepatitis B virus replication, resulting in low viral replication. This dataset is part of the TransQST collection.

ORGANISM(S): Homo sapiens

SUBMITTER: Jiming Zhang

PROVIDER: E-GEOD-65359 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored. Methods: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. Results: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. Conclusions: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle. The Oxylipin assay and the Lipid assays for this study can be found in the MetaboLights studies MTBLS253 and MTBLS279 respectively.

Project description:Background: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored. Methods: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. Results: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. Conclusions: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle. The Lipid assays and the Biogenic amine and Acyl-carnitine assays for this study can be found in the MetaboLights studies MTBLS279 and MTBLS280 respectively.

Project description:Background: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored. Methods: To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. Results: Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. Conclusions: The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle. The Oxylipin assay and the Biogenic amine and Acyl-carnitine assays for this study can be found in the MetaboLights studies MTBLS253 and MTBLS280 respectively.

Project description:Purpose: Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive hepatic diseases (hepatitis, cirrhosis or liver cancer). Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection to liver disease remains unexplored. Thus, the aim of our study was to determine the serum metabolic characteristics of hepatic disease patients with chronic hepatitis B in active and inactive stage and study the influence of active and inactive stage of the chronic hepatitis B virus on the development of liver cancer by untargeted metabolomics. Method: To investigate this, we conducted an untargeted metabolomics approach to determine the metabolic characteristics of 199 human serum samples from hepatic disease patients in active and inactive chronic HBV via UHPLC-Q-TOF/MS, and patients with HBV in active or inactive stage were grouped based on their serum levels of HBV DNA and HBV envelope antigen (HBeAg). Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and volcano plot were used for multivariate analysis. Pathway analysis were conducted according to p-values from pathway enrichment analysis and pathway impact values from pathway topology analysis. In addition, commercial databases were used to identify metabolites from significantly altered metabolic pathways. All samples were analyzed for liver function tests indicated the levels of certain enzymes. Results: Our data provide insight into the metabolic dysregulation experienced during active or inactive stage of the HBV on the development of liver disease, and analysis of serum metabolomic profiles indicated that most of the altered metabolic pathways for chronic hepatitis and cirrhosis patients with active or inactive stage of the HBV were associated with D-Glutamine and D-glutamate metabolism, indicating a strong link to HBV replication (p < 0.05). In addition, liver function analysis showed the enzymes gamma-glutamyl transferase (GGT) were increased concomitant to the progression of hepatitis to cirrhosis induced by chronic HBV (p < 0.05).

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Liver transcriptome profiles correlates with viral control during hepatitis B virus infection

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