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

• Verfasst von: Gruber, Sabine [VerfasserIn]
• Verfasst von: Straub, Beate Katharina [VerfasserIn]
• Verfasst von: Schirmacher, Peter [VerfasserIn]
• Titel: Obesity promotes liver carcinogenesis via Mcl-1 stabilization independent of IL-6Rα signaling
• Verf.angabe: 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, and F. Thomas Wunderlich
• E-Jahr: 2013
• Jahr: 15 August 2013
• Umfang: 12 S.
• Fussnoten: Im Titel wird alpha als griechischer Buchstabe dargestellt ; Gesehen am 29.01.2021
• Titel Quelle: Enthalten in: Cell reports
• Ort Quelle: Maryland Heights, MO : Cell Press, 2012
• Jahr Quelle: 2013
• Band/Heft Quelle: 4(2013), 4, Seite 669-680
• ISSN Quelle: 2211-1247
• DOI: doi:10.1016/j.celrep.2013.07.023
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1745927409

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.