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A02: Hepatitis C virus induced dysregulation of lipid metabolism and implications for HCC development

Infection with the hepatitis C virus (HCV) is an important risk factor for the development of hepatocellular carcinoma (HCC). Although antiviral therapy to treat chronic hepatitis C eliminates the virus in most patients, the risk for HCC development remains, at least in patients with advanced cirrhosis, and some studies indicate that the risk might even increase. The aim of this proposal is to study distinct aspects of HCV-associated pathogenesis likely contributing to HCC formation. While chronic inflammation, induced by HCV is a widely accepted cofactor promoting HCC development, here we will focus on more direct protumorigenic contributions of HCV. For instance we found that HCV perturbs lipid homeostasis, thus contributing to hepatic steatosis, which is an important risk factor for HCC. Moreover, we found that HCV induces the release of fibrogenic cytokines, most notably TGF-β1 from infected cells, sequesters tumor suppressors such as DDX3, ANXA2, hnRNP-K and miR-122 and causes profound alterations of intracellular phosphatidylinositol 4-phosphate (PI4P) distribution, thus altering cellular signaling potentially contributing to HCC development or progression. Building on these results, in the present proposal we will address two major goals. The first one aims to characterize the molecular mechanisms how viral hepatosteatosis and fibrosis are induced by HCV. We will also determine the mechanism by which cofactors such as chronic inflammation and high fat diet contribute to these processes by using infection-based cell culture systems and state-of-the art mouse models. The second goal aims to clarify the pathogenic consequences of HCV-induced activation of the cellular pathways governed by the lipid kinase Phosphatidylinositol 4-kinase IIIα, which plays a key role in phosphatidylinositide metabolism and which is overexpressed in HCC. This includes studying the consequences of elevated PI4P levels in the context of inflammatory processes in the liver. Infection with HCV is a paradigm for hepatosteatosis and chronic inflammation and thus, the studies proposed here will provide important insights how these processes are linked to HCC development in general.


a) Peer-reviewed publications and books
• Lupberger J, Croonenborghs T, Roca Suarez AA, Van Renne N, Jühling F, Oudot MA, Virzì A, Bandiera S, Jamey C, Meszaros G, Brumaru D, Mukherji A, Durand SC, Heydmann L, Verrier ER, El Saghire H, Hamdane N, Bartenschlager R, Fereshetian S, Ramberger E, Sinha R, Nabian M, Everaert C, Jovanovic M, Mertins P, Carr SA, Chayama K, Dali-Youcef N, Ricci R, Bardeesy NM, Fujiwara N, Gevaert O, Zeisel MB, Hoshida Y, Pochet N, Baumert TF (2019) Combined analysis of metabolomes, proteomes, and transcriptomes of hepatitis C virus-infected cells and liver to identify pathways associated with disease development. Gastroenterology 157:537-551.
• Levander S, Holmstrom F, Frelin L, Ahlén G, Rupp D, Long G, Bartenschlager R*, Sällberg, M* (2018) Immune-mediated effects targeting hepatitis C virus in a syngeneic replicon cell transplantation mouse model. Gut 67:1525-1535. *equal senior correspondence.
b) Other publications, both peer-reviewed and non-peer-reviewed
• Lohmann V, Bartenschlager R (2019) Indelibly stamped by hepatitis C virus infection: persistent epigenetic signatures increasing liver cancer risk. Gastroenterology 156:2130-2133.
• Lee JS, Tabata K, Twu WI, Rahman MS, Kim HS, Yu JB, Jee MH, Bartenschlager R, Jang SK (2019) RACK1 mediates rewiring of intracellular networks induced by hepatitis C virus infection. PLoS Pathog 15:e1008021.
• Lee JY, Cortese M, Haselmann U, Tabata K, Romero-Brey I, Funaya C, Schieber NL, Qiang Y, Bartenschlager M, Kallis S, Ritter C, Rohr K, Schwab Y, Ruggieri A, Bartenschlager R (2019) Spatiotemporal coupling of the hepatitis C virus replication cycle by creating a lipid droplet-proximal membranous replication compartment. Cell Rep 27:3602-3617.
• Stoeck IK, Lee JY, Tabata K, Romero-Brey I, Paul D, Schult P, Lohmann V, Kaderali L, Bartenschlager R (2017) Hepatitis C virus replication depends on endosomal cholesterol homeostasis. J Virol 92:e01196-17.
• Tu T, Bühler S, Bartenschlager R (2017) Chronic viral hepatitis and its association with liver cancer. Biol Chem 398:817-837.
• Harak C, Meyrath M, Romero-Brey I, Schenk C, Gondeau C, Schult P, Esser-Nobis K, Saeed M, Neddermann P, Schnitzler P, Gotthardt D, Perez-Del-Pulgar S, Neumann-Haefelin C, Thimme R, Meuleman P, Vondran FW, De Francesco R, Rice CM, Bartenschlager R, Lohmann V (2016) Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture. Nat Microbiol 2:16247.