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Obesity promotes liver carcinogenesis via Mcl-1 stabilization independent of IL-6Rα signaling

Obesity increases the incidence of hepatocellular carcinoma (HCC) development in part through the activation of obesity-associated proinflammatory signaling. Here, we show that in lean mice, abrogation of IL-6Rα signaling protects against diethylnitrosamine (DEN)-induced HCC development. HCC protect...

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Bibliographic Details
Main Authors: Gruber, Sabine (Author) , Straub, Beate Katharina (Author) , Schirmacher, Peter (Author)
Format: Article (Journal)
Language:English
Published: 15 August 2013
In: Cell reports
Year: 2013, Volume: 4, Issue: 4, Pages: 669-680
ISSN:2211-1247
DOI:10.1016/j.celrep.2013.07.023
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.celrep.2013.07.023
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124713003859
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Author Notes:Sabine Gruber, Beate K. Straub, P. Justus Ackermann, Claudia M. Wunderlich, Jan Mauer, Jens M. Seeger, Hildegard Büning, Lukas Heukamp, Hamid Kashkar, Peter Schirmacher, Jens C. Brüning, and F. Thomas Wunderlich
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Summary:Obesity increases the incidence of hepatocellular carcinoma (HCC) development in part through the activation of obesity-associated proinflammatory signaling. Here, we show that in lean mice, abrogation of IL-6Rα signaling protects against diethylnitrosamine (DEN)-induced HCC development. HCC protection occurs via Mcl-1 destabilization, thus promoting hepatocyte apoptosis. IL-6 regulates Mcl-1 stability via the inhibition of PP-1α expression, promoting GSK-3β inactivation. In addition, IL-6 suppresses expression of the Mcl-1 E3 ligase (Mule). Consequently, IL-6Rα deficiency activates PP-1α and Mule expression, resulting in increased Mcl-1 turnover and protection against HCC development. In contrast, in obesity, inhibition of PP-1α and Mule expression, leading to Mcl-1 stabilization, occurs independently of IL-6 signaling. Collectively, this study provides evidence that obesity inhibits hepatocyte apoptosis through Mcl-1 stabilization independent of IL-6 signaling, thus promoting liver carcinogenesis.
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Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2013.07.023

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