Combined Analysis of Metabolomes, Proteomes, and Transcriptomes of Hepatitis C Virus-Infected Cells and Liver to Identify Pathways Associated With Disease Development.
Animals
Cell Line, Tumor
Datasets as Topic
Disease Models, Animal
Gene Expression Profiling
Glucose
/ metabolism
Hepacivirus
/ pathogenicity
Hepatitis C, Chronic
/ metabolism
Hepatocytes
/ pathology
Humans
Liver
/ cytology
Metabolomics
Mice
Peroxisomes
/ metabolism
Proteomics
STAT3 Transcription Factor
/ metabolism
Transplantation Chimera
HCC
immune regulation
metabolic disease
signal transduction
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
03
08
2018
revised:
01
03
2019
accepted:
04
04
2019
pubmed:
13
4
2019
medline:
27
8
2019
entrez:
13
4
2019
Statut:
ppublish
Résumé
The mechanisms of hepatitis C virus (HCV) infection, liver disease progression, and hepatocarcinogenesis are only partially understood. We performed genomic, proteomic, and metabolomic analyses of HCV-infected cells and chimeric mice to learn more about these processes. Huh7.5.1 We quantified 21,950 messenger RNAs (mRNAs) and 8297 proteins in HCV-infected cells. Upon HCV infection of hepatocyte-like cells and chimeric mice, we observed significant changes in levels of mRNAs and proteins involved in metabolism and hepatocarcinogenesis. HCV infection of hepatocyte-like cells significantly increased levels of the mRNAs, but not proteins, that regulate the innate immune response; we believe this was due to the inhibition of translation in these cells. HCV infection of hepatocyte-like cells increased glucose consumption and metabolism and the STAT3 signaling pathway and reduced peroxisome function. Peroxisomes mediate β-oxidation of very long-chain fatty acids; we found intracellular accumulation of very long-chain fatty acids in HCV-infected cells, which is also observed in patients with fatty liver disease. Cells in livers from HCV-infected mice had significant reductions in levels of the mRNAs and proteins associated with peroxisome function, indicating perturbation of peroxisomes. We found that defects in peroxisome function were associated with outcomes and features of HCV-associated cirrhosis, fatty liver disease, and hepatocellular carcinoma in patients. We performed combined transcriptome, proteome, and metabolome analyses of liver tissues from HCV-infected hepatocyte-like cells and HCV-infected mice. We found that HCV infection increases glucose metabolism and the STAT3 signaling pathway and thereby reduces peroxisome function; alterations in the expression levels of peroxisome genes were associated with outcomes of patients with liver diseases. These findings provide insights into liver disease pathogenesis and might be used to identify new therapeutic targets.
Sections du résumé
BACKGROUND & AIMS
The mechanisms of hepatitis C virus (HCV) infection, liver disease progression, and hepatocarcinogenesis are only partially understood. We performed genomic, proteomic, and metabolomic analyses of HCV-infected cells and chimeric mice to learn more about these processes.
METHODS
Huh7.5.1
RESULTS
We quantified 21,950 messenger RNAs (mRNAs) and 8297 proteins in HCV-infected cells. Upon HCV infection of hepatocyte-like cells and chimeric mice, we observed significant changes in levels of mRNAs and proteins involved in metabolism and hepatocarcinogenesis. HCV infection of hepatocyte-like cells significantly increased levels of the mRNAs, but not proteins, that regulate the innate immune response; we believe this was due to the inhibition of translation in these cells. HCV infection of hepatocyte-like cells increased glucose consumption and metabolism and the STAT3 signaling pathway and reduced peroxisome function. Peroxisomes mediate β-oxidation of very long-chain fatty acids; we found intracellular accumulation of very long-chain fatty acids in HCV-infected cells, which is also observed in patients with fatty liver disease. Cells in livers from HCV-infected mice had significant reductions in levels of the mRNAs and proteins associated with peroxisome function, indicating perturbation of peroxisomes. We found that defects in peroxisome function were associated with outcomes and features of HCV-associated cirrhosis, fatty liver disease, and hepatocellular carcinoma in patients.
CONCLUSIONS
We performed combined transcriptome, proteome, and metabolome analyses of liver tissues from HCV-infected hepatocyte-like cells and HCV-infected mice. We found that HCV infection increases glucose metabolism and the STAT3 signaling pathway and thereby reduces peroxisome function; alterations in the expression levels of peroxisome genes were associated with outcomes of patients with liver diseases. These findings provide insights into liver disease pathogenesis and might be used to identify new therapeutic targets.
Identifiants
pubmed: 30978357
pii: S0016-5085(19)35670-7
doi: 10.1053/j.gastro.2019.04.003
pmc: PMC8318381
mid: NIHMS1723772
pii:
doi:
Substances chimiques
STAT3 Transcription Factor
0
STAT3 protein, human
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Pagination
537-551.e9Subventions
Organisme : NCI NIH HHS
ID : R21 CA209940
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI123862
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099558
Pays : United States
Organisme : NIAID NIH HHS
ID : R03 AI131066
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214846
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233794
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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