| First Author | Gruber S | Year | 2013 |
| Journal | Cell Rep | Volume | 4 |
| Issue | 4 | Pages | 669-80 |
| PubMed ID | 23954788 | Mgi Jnum | J:202764 |
| Mgi Id | MGI:5521424 | Doi | 10.1016/j.celrep.2013.07.023 |
| Citation | Gruber S, et al. (2013) Obesity promotes liver carcinogenesis via Mcl-1 stabilization independent of IL-6Ralpha signaling. Cell Rep 4(4):669-80 |
| abstractText | 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-6Ralpha 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-1alpha expression, promoting GSK-3beta inactivation. In addition, IL-6 suppresses expression of the Mcl-1 E3 ligase (Mule). Consequently, IL-6Ralpha deficiency activates PP-1alpha and Mule expression, resulting in increased Mcl-1 turnover and protection against HCC development. In contrast, in obesity, inhibition of PP-1alpha 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. |
