Tumor cell-like metabolic adaptations in the pathophysiology of chronic viral hepatitis
Chronic infection with hepatitis B and C and D viruses (HBV/ HCV/HDV) is one of the main etiologies of hepatocellular carcinoma (HCC), the most common form of liver cancer. A major feature of chronic viral hepatitis is the frequent occurrence of oxidative stress and metabolic alterations, which play a major role in liver fibrosis and disease progression towards liver cancer.
At the interface between virology, cell biology and biochemistry, our laboratory is analyzing metabolic alterations and associated intracellular oxidative stress induced by hepatitis viruses and their respective roles in the development of liver fibrosis. We have found for example evidence for the installation of a tumor cell-like metabolism in HCV-infected cells, characterized by a special dependence on glutamine utilization.
Importantly, altered glutamine fluxes impact mitochondria and mitochondrial functions and may alter cellular resistance to apoptosis, inflammatory processes, metabolic and redox homeostasis in infected cells and is thus potentially strongly pro-carcinogenic.
Our particular aims are:
To show how hepatitis viruses modulate metabolic fluxes using biochemistry, molecular biology and metabolomics
To investigate how hepatitis viruses impact and alter mitochondrial structure and functions, via direct binding to these organelles or by altered function of mitochondrial or metabolic enzymes
Investigate how hepatitis virus-induced metabolic changes are linked to increased oxidative stress frequently observed in infection in vitro and in patients
To investigate how the above events drive fibrosis progression and hepatocarcinogenesis in infected patients
To find answers to these questions, we use a mixture of molecular and cellular biology, biochemistry, metabolomics, imaging and state of the art infection assays (P3 biosafety level). In addition, we have access to clinical cohorts and samples.
These studies will on the long term lead to the development of biomarkers and optimization of treatment modalities for fibrosis progression and prevention of hepatocarcinogenesis in viral hepatitis.
Selected publications from 2015-2017 :
AV Ivanov, O Khomich, B Bartosch. Oxidative Stress in Hepatitis C infection; Bookchapter in Liver Oxidative Stress and Dietary Antioxidants, edited by Vinood Patel. Elsevier. In press
O. Smirnova, T. Keinanen, O. Ivanova M. Hyvonen, A. Khomutov, S. Kochetkov, B. Bartosch, and A. Ivanov Hepatitis C virus Alters metabolism of biogenic polyamines by affecting expression of key enzymes of their metabolism 2017 BBRC
AV Ivanov, VT Valuev-Elliston, DA Tyurina, ON Ivanova, SN Kochetkov, B Bartosch, MG Isaguliants Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis. 2017 Oncotarget
P.L. Lévy, S. Duponchel, H. Eischeid, M. Michelet, J. Molle, HP. Dienes, HM. Steffen, M. Odenthal, F. Zoulim, B. Bartosch. Hepatitis C virus infection triggers a tumor-like glutamine metabolism. 2017 Hepatology
A V. Ivanov, V T. Valuev-Elliston, O Ivanova, S N. Kochetkov, B Bartosch and M G. Isaguliants. Oxidative stress during HIV infection: mechanisms and consequences. 2016 Oxid Med Cell Longev
J Rieusset , J Fauconnier, M Paillard , E Belaidi , E Tubbs , M-A Chauvin, A Durand , A Bravard , G Teixeira , B Bartosch , M Michelet, P Theurey , G Vial , M Demion, E Blond , F Zoulim , L Gomez , H Vidal , A Lacampagne, M Ovize. Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated endoplasmic reticulum membranes (MAM) integrity to hepatic insulin resistance. 2016 Diabetologia
Charlène Brault, Pierre Lévy, Sarah Duponchel, Maud Michelet, Aurèlie Sallé, Eve-Isabelle Pecheur, Marie-Laure Plissonnier, Romain Parent, Evelyne Véricel, Alexander V Ivanov, Münevver Demir, Hans-Michael Steffen, Margarete Odenthal, Fabien Zoulim, Birke Bartosch. Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity. 2016 Gut
Pierre Lévy, Birke Bartosch, Metabolic reprogramming: a hallmark of viral oncogenesis. 2015 Oncogene