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 PMID:23954788  

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

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 | F Thomas Wunderlich
Cell reports | 2013

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.

Pubmed ID: 23954788

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