Hepatitis C virus infection triggers a tumor-like glutamine metabolism

Lévy, Pierre L.; Duponchel, Sarah; Eischeid, Hannah; Molle, Jennifer; Michelet, Maud; Diserens, Gaëlle; Vermathen, Martina; Vermathen, Peter; Dufour, Jean-François; Dienes, Hans-Peter; Steffen, Hans-Michael; Odenthal, Margarete; Zoulim, Fabien; Bartosch, Birke (2017). Hepatitis C virus infection triggers a tumor-like glutamine metabolism. Hepatology, 65(3), pp. 789-803. Wiley Interscience 10.1002/hep.28949

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Chronic infection with hepatitis C virus (HCV) is one of the main causes of hepatocellular carcinoma. However, the molecular mechanisms linking the infection to cancer development remain poorly understood. Here we used HCV-infected cells and liver biopsies to study how HCV modulates the glutaminolysis pathway, which is known to play an important role in cellular energetics, stress defense and neoplastic transformation. Transcript levels of glutaminolytic factors were quantified in Huh7.5 cells or primary human hepatocytes infected with the JFH1 HCV strain as well as in biopsies of chronic HCV patients. Nutrient deprivation, biochemical analysis and metabolite quantification were performed with JFH1 infected Huh7.5 cells. Furthermore, shRNA vectors and small molecule inhibitors were used to investigate the dependence of HCV replication on metabolic changes. We show that HCV modulates the transcript levels of key enzymes of the glutamine metabolism in vitro and in liver biopsies of chronic HCV patients. Consistently, HCV infection increases glutamine utilization and dependence. We finally show that inhibiting glutamine metabolism attenuates HCV infection and the oxidative stress associated with HCV infection. Conclusions: Our data suggest that HCV establishes glutamine dependence, which is required for viral replication. Importantly, glutamine addiction is also a hallmark of tumor cells. While HCV induces glutaminolysis to create an environment favorable for viral replication, it predisposes the cell to transformation. Glutaminolytic enzymes may be interesting therapeutic targets for prevention of hepatocarcinogenesis in chronic hepatitis C.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

08 Faculty of Science > Departement of Chemistry and Biochemistry
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Pavillon 52 > Abt. Magnetresonanz-Spektroskopie und Methodologie, AMSM
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Diserens, Gaëlle; Vermathen, Martina; Vermathen, Peter and Dufour, Jean-François

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry
600 Technology > 610 Medicine & health

ISSN:

0270-9139

Publisher:

Wiley Interscience

Language:

English

Submitter:

Martina Vermathen

Date Deposited:

24 Jan 2017 11:00

Last Modified:

19 Nov 2017 02:30

Publisher DOI:

10.1002/hep.28949

PubMed ID:

27863447

BORIS DOI:

10.7892/boris.92486

URI:

https://boris.unibe.ch/id/eprint/92486

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