Obesity and IL-6 promote liver carcinogenesis via Mcl-1 stabilization

Obesity is a constantly increasing health burden affecting more than 30% of inhabitants of westernized populations. In addition to classical associated disorders, obesity was also previously reported to increase the incidence of hepatocellular carcinoma (HCC) development. One possible reason for why obesity is associated with HCC development is that this condition also triggers higher serum levels of the inflammatory cytokines TNFα and IL-6. However, how these inflammatory cytokines are connected with HCC development is currently not fully understood. Here we report that obesity-associated inflammation provokes HCC progression by inhibiting hepatocyte apoptosis as a consequence of Mcl-1 stabilization. Inhibition of apoptosis was found to occur after IL-6-stimulated GSK-3b serine-9 phosphorylation and inactivation, which in turn led to the stabilization of the anti-apoptotic Bcl-2-family-member Mcl-1. Moreover, increased IL-6 level under obese conditions led to the transcriptional suppression of the Mcl-1 ubiquitin ligase E3 (Mule) further stabilizing Mcl-1 in obese mice. Interestingly, while IL-6Ra-deficiency protects against diethylnitrosamine-induced HCC development in lean mice, obesity-induced activation of this pathway even overrides the protective effect of IL-6Ra-deficiency on HCC development. Collectively, this study provides evidence that obesity plays a critical role in hepatocyte apoptosis thereby affecting HCC development and progression.