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Hepatitis C virus and glucose and lipid metabolism: molecular interactions and significance

English title Hepatitis C virus and glucose and lipid metabolism: molecular interactions and significance
Applicant Negro Francesco
Number 166609
Funding scheme Project funding (special)
Research institution Service de Gastroentérologie Hopitaux Universitaires de Genève
Institution of higher education University of Geneva - GE
Main discipline Pathophysiology
Start/End 01.04.2016 - 31.03.2019
Approved amount 430'500.00
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Keywords (5)

liver fibrosis; hepatitis C; insulin resistance; hepatocellular carcinoma; liver steatosis

Lay Summary (French)

Lead
Le virus de l’hépatite C (VHC) est un agent pathogène humain qui cause une inflammation hépatique chronique pouvant évoluer vers la cirrhose, le carcinome primaire du foie et plusieurs complications extrahépatiques, comme un diabète de type 2. Le VHC infecte environ 3% de la population mondiale et ses complications sont responsables d’environ 350'000 decès par an. Les traitements actuels, bien que très coûteux, sont très efficaces, et permettent l’éradication définitive de l’infection, ce qui conduit à une amélioration significative de la morbilité et de la mortalité associées au VHC.
Lay summary

L’infection par VHC est caractérisée par de nombreuses interactions avec le metabolisme lipidique et glucidique de l’hôte, conduisant à une stéatose (infiltrationn graisseuse du foie) et à une insulino-résistance. Nos recherches ont comme but la compréhension des mécanismes soujacents ces interactions, ainsi que de leurs conséquences au niveau du foie (p.ex. la progression de la fibrose et la survenue d’un carcinome primaire du foie) et, plus en général, du métabolisme de l’hôte. Nous estimons que la connaissance de ces mécanismes pourra nous aider à émettre des hypothèses de travail et ainsi mieux étudier la pathogenèse et l’histoire naturelle d’autres maladies, telles que la stéato-hépatite non-alcoolique et le diabète de type 2.

Le projet relève de la recherche clinique et translationnelle. Nous souhaitons utiliser nos connaissances des mécanismes de maladie hépatique et extrahépatique lors d’une infection par VHC pour mieux étudier d’autres maladies caractérisées par les mêmes altérations métaboliques.

Direct link to Lay Summary Last update: 29.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Treatment with direct-acting antivirals improves peripheral insulin sensitivity in non-diabetic, lean chronic hepatitis C patients
Gastaldi Giacomo, Gomes Diana, Schneiter Philippe, Montet Xavier, Tappy Luc, Clément Sophie, Negro Francesco (2019), Treatment with direct-acting antivirals improves peripheral insulin sensitivity in non-diabetic, lean chronic hepatitis C patients, in PLOS ONE, 14(6), e0217751-e0217751.
Activation of the oncogenic miR‐21‐5p promotes HCV replication and steatosis induced by the viral core 3a protein
Clément Sophie, Sobolewski Cyril, Gomes Diana, Rojas Angela, Goossens Nicolas, Conzelmann Stéphanie, Calo Nicolas, Negro Francesco, Foti Michelangelo (2019), Activation of the oncogenic miR‐21‐5p promotes HCV replication and steatosis induced by the viral core 3a protein, in Liver International, liv.14112-liv.14112.
Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review
Goossens N., de Vito C., Mangia A., Clément S., Cenderello G., Barrera F., D'Ambrosio R., Coppola N., Zampino R., Stanzione M., Adinolfi L. E., Wedemeyer H., Semmo N., Müllhaupt B., Semela D., Malinverni R., Moradpour D., Heim M., Trincucci G., Rubbia-Brandt L., Negro F. (2018), Effect of hepatitis B virus on steatosis in hepatitis C virus co-infected subjects: A multi-centre study and systematic review, in Journal of Viral Hepatitis.
Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance
Brenachot Xavier, Ramadori Giorgio, Ioris Rafael M., Veyrat-Durebex Christelle, Altirriba Jordi, Aras Ebru, Ljubicic Sanda, Kohno Daisuke, Fabbiano Salvatore, Clement Sophie, Goossens Nicolas, Trajkovski Mirko, Harroch Sheila, Negro Francesco, Coppari Roberto (2017), Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance, in Nature Communications, 8(1), 1820-1820.
Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets
Rojas Ángela, Del Campo Jose A., Clement Sophie, Lemasson Matthieu, García-Valdecasas Marta, Gil-Gómez Antonio, Ranchal Isidora, Bartosch Birke, Bautista Juan D., Rosenberg Arielle R., Negro Francesco, Romero-Gómez Manuel (2016), Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets, in Scientific Reports, 6(1), 31777-31777.

Collaboration

Group / person Country
Types of collaboration
Roberto Coppari, Dept. Cellular Physiology and Metabolism, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Michelangelo Foti, PhD, Dept. Cellular Physiology and Metabolism, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Luc Tappy, MD, Diabetology, CHUV, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Howard Riezman, PhD, Dept. of Biochemistry and NCCR Chemical Biology, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Pharmacy of Centre Hospitalier Universitaire Vaudois (CHUV) Switzerland (Europe)
- Research Infrastructure
Eric O. Potma, PhD, Chemistry, University of California at Irvine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Swiss Hepatitis C Cohort Study Group Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Charna Dibner, PhD, Endocrinology, University Hospital of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Jacques Philippe, MD/Giacomo Gastaldi, MD, Diabetology, University Hospitals of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Awards

Title Year
Fondation pour la Recherche sur le Diabète 2016

Associated projects

Number Title Start Funding scheme
177521 The Swiss Hepatitis C Cohort Study 01.01.2018 Cohort Studies Large
152618 PTEN signaling in metabolic liver diseases and crosstalk to peripheral organs 01.04.2014 Project funding (Div. I-III)
146991 Hepatitis C virus and glucose and lipid metabolism: molecular interactions and significance 01.04.2013 Project funding (special)
184663 Hepatitis C virus infection as a model for hepatogenous glucose homeostasis alterations 01.04.2019 Project funding (Div. I-III)

Abstract

Hepatitis C virus (HCV) is a member of the Flaviviridae family and a major cause of chronic liver disease worldwide, infecting an estimated 3% of the global population. Morbidity and mortality associated with HCV are not only due to the end-stage sequelae of chronic hepatitis, including decompensated cirrhosis and hepatocellular carcinoma, but also to a vast range of extrahepatic disorders, encompassing cryoglobulinemia-associated syndrome, insulin resistance (IR)/type 2 diabetes, and cardiovascular outcomes. Treatment of HCV may lead to permanent cure of the infection, with beneficial effects on both liver- and non-liver-related outcomes. The physiopathology of HCV infection is characterized by several interactions with the host cell lipid and glucose metabolism, causing respectively steatosis and insulin resistance (IR), two pathologic features shared by the non-alcoholic fatty liver disease (NAFLD), i.e. the liver feature of the metabolic syndrome. Both steatosis and IR induced by HCV may play a role in clinical outcomes associated with hepatitis C. In this proposal, we aim to analyse in detail some aspects of the molecular physiopathology of these interactions. We think that identifying these mechanisms of disease may be useful to put forward working hypotheses (and set up experimental models) to study liver disorders other than hepatitis C, such as NAFLD or type 2 diabetes. In particular, we plan to analyse (i) the role of specific lipid species (e.g. sphingolipids) in liver disease progression, (ii) the mechanisms underlying the HCV-associated downregulation of the tumor suppression PTEN, and whether this may predict metabolic disorders and HCC development in the natural course of hepatitis C; (iii) the relative contribution of hepatic vs. extrahepatic sites (e.g. striated muscle) in the pathogenesis of IR in hepatitis C, via the complete viral suppression induced by specific antiviral drugs. In an additional subproject, based on our recent findings, we will also study how lipid accumulation may affect tight junction expression and function: the results of this part of the proposal may not only shed new light on a poorly studied aspect of cell biology, but also be relevant in understanding hepatocarcinogenesis. Thus, we think that unravelling the mechanisms underlying the metabolic alterations induced by HCV may not only improve our knowledge about HCV pathogenesis, but also provide the rationale for working hypotheses aimed at understanding other chronic liver disorders - such as NAFLD - or even type 2 diabetes and their cardiovascular outcomes.
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