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Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation

Chatzigeorgiou, Antonios; Chung, Kyoung-Jin; Garcia-Martin, Ruben; Alexaki, Vasileia-Ismini; Klotzsche-von Ameln, Anne; Phieler, Julia; Sprott, David; Kanczkowski, Waldemar; Tzanavari, Theodora; Bdeir, Mohktar; Bergmann, Sibylle; Cartellieri, Marc; Bachmann, Michael; Nikolakopoulou, Polyxeni; Androutsellis-Theotokis, Andreas; Siegert, Gabriele; Bornstein, Stefan R.; Muders, Michael H.; Boon, Louis; Karalis, Katia P.; Lutgens, Esther; Chavakis, Triantafyllos

Authors

Antonios Chatzigeorgiou

Kyoung-Jin Chung

Ruben Garcia-Martin

Vasileia-Ismini Alexaki

Anne Klotzsche-von Ameln

Julia Phieler

David Sprott

Waldemar Kanczkowski

Theodora Tzanavari

Mohktar Bdeir

Sibylle Bergmann

Marc Cartellieri

Michael Bachmann

Polyxeni Nikolakopoulou

Andreas Androutsellis-Theotokis

Gabriele Siegert

Stefan R. Bornstein

Michael H. Muders

Louis Boon

Katia P. Karalis

Esther Lutgens

Triantafyllos Chavakis



Abstract

The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibody-blockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. Conclusion: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesity-related metabolic dysregulation and, especially, NASH

Journal Article Type Article
Publication Date Sep 22, 2014
Journal Hepatology
Print ISSN 0270-9139
Electronic ISSN 1527-3350
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 60
Issue 4
APA6 Citation Chatzigeorgiou, A., Chung, K., Garcia-Martin, R., Alexaki, V., Klotzsche-von Ameln, A., Phieler, J., …Chavakis, T. (2014). Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology, 60(4), https://doi.org/10.1002/hep.27233
DOI https://doi.org/10.1002/hep.27233
Keywords liver steatosis, adipose tissue, regulatory T cells, inflammation
Publisher URL http://dx.doi.org/10.1002/hep.27233
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This is the peer reviewed version of the following article: Chatzigeorgiou, A., Chung, K.-J., Garcia-Martin, R., Alexaki, V.-I., Klotzsche-von Ameln, A., Phieler, J., Sprott, D., Kanczkowski, W., Tzanavari, T., Bdeir, M., Bergmann, S., Cartellieri, M., Bachmann, M., Nikolakopoulou, P., Androutsellis-Theotokis, A., Siegert, G., Bornstein, S. R., Muders, M. H., Boon, L., Karalis, K. P., Lutgens, E. and Chavakis, T. (2014), Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology, 60: 1196–1210, which has been published in final form at doi:10.1002/hep.27233. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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