The summaries are free for public
use. The Chronic Liver Disease
Foundation will continue to add and
archive summaries of articles deemed
relevant to CLDF by the Board of
Trustees and its Advisors.
Abstract Details
Obesity promotes liver carcinogenesis via Mcl-1 stabilization independent of IL-6Rα signaling
Gruber S, Straub BK, Ackermann PJ, Wunderlich CM, Mauer J, Seeger JM, Büning H, Heukamp L, Kashkar H, Schirmacher P, Brüning JC, Wunderlich FT. Cell Rep. 2013 Aug 29;4(4):669-80. doi: 10.1016/j.celrep.2013.07.023. Epub 2013 Aug 15.
Source
Max Planck Institute for Neurological Research Cologne, Institute for Genetics, University of Cologne, 50937 Cologne, Germany.
Abstract
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.