Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling

•Obesity increases hepatocellular carcinoma (HCC) via Mcl-1 stabilization•IL-6Rα deficiency protects against HCC development in lean mice•Obesity accelerates HCC development even in the absence of IL-6Rα signaling•Obesity inhibits apoptosis via inhibition of GSK-3β and Mule

SummaryObesity 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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