Universität zu Köln

Levy, Pierre L., Duponchel, Sarah, Eischeid, Hannah, Molle, Jennifer, Michelet, Maud, Diserens, Gaeelle, Vermathen, Martina ORCID: 0000-0002-0796-1643, Vermathen, Peter, Dufour, Jean-Francois, Dienes, Hans-Peter, Steffen, Hans-Michael, Odenthal, Margarete, Zoulim, Fabien ORCID: 0000-0002-2245-0083 and Bartosch, Birke ORCID: 0000-0001-6354-4660 (2017). Hepatitis C Virus Infection Triggers a Tumor-Like Glutamine Metabolism. Hepatology, 65 (3). S. 789 - 804. HOBOKEN: WILEY. ISSN 1527-3350

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Abstract

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 HCVinfected 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 Japanese fulminant hepatitis 1 HCV strain as well as in biopsies of chronic HCV patients. Nutrient deprivation, biochemical analysis, and metabolite quantification were performed with HCV-infected Huh7.5 cells. Furthermore, short hairpin RNA 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 glutamine metabolism in vitro and in liver biopsies of chronic HCV patients. Consistently, HCV infection increases glutamine use and dependence. We finally show that inhibiting glutamine metabolism attenuates HCV infection and the oxidative stress associated with HCV infection. Conclusion: Our data suggest that HCV establishes glutamine dependence, which is required for viral replication, and, importantly, that glutamine addiction is 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
Creators:	Creators Email ORCID ORCID Put Code Levy, Pierre L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Duponchel, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Eischeid, Hannah UNSPECIFIED UNSPECIFIED UNSPECIFIED Molle, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Michelet, Maud UNSPECIFIED UNSPECIFIED UNSPECIFIED Diserens, Gaeelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermathen, Martina UNSPECIFIED orcid.org/0000-0002-0796-1643 UNSPECIFIED Vermathen, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Dufour, Jean-Francois UNSPECIFIED UNSPECIFIED UNSPECIFIED Dienes, Hans-Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Steffen, Hans-Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED Zoulim, Fabien UNSPECIFIED orcid.org/0000-0002-2245-0083 UNSPECIFIED Bartosch, Birke UNSPECIFIED orcid.org/0000-0001-6354-4660 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-238533
DOI:	10.1002/hep.28949
Journal or Publication Title:	Hepatology
Volume:	65
Number:	3
Page Range:	S. 789 - 804
Date:	2017
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1527-3350
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CANCER METABOLISM; PYRUVATE-KINASE; GROWTH; REPLICATION; HYPOXIA; CELLS; PATHWAY; CARBOXYLATION; TRANSPORTERS; TRANSLATION Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23853