title: Obesity promotes liver carcinogenesis via Mcl-1 stabilization independent of IL-6Rα signaling.
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.
authors: Max Planck Institute for Neurological Research Cologne, Institute for Genetics, University of Cologne, 50937 Cologne, Germany.
authors: Sabine
authors: S
authors: Gruber
authors: Beate K
authors: BK
authors: Straub
authors: P Justus
authors: PJ
authors: Ackermann
authors: Claudia M
authors: CM
authors: Wunderlich
authors: Jan
authors: J
authors: Mauer
authors: Jens M
authors: JM
authors: Seeger
authors: Hildegard
authors: H
authors: Büning
authors: Lukas
authors: L
authors: Heukamp
authors: Hamid
authors: H
authors: Kashkar
authors: Peter
authors: P
authors: Schirmacher
authors: Jens C
authors: JC
authors: Brüning
authors: F Thomas
authors: FT
authors: Wunderlich
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019947:Receptors, Interleukin-6; D025521:Tumor Suppressor Proteins; C113250:interleukin-6 receptor alpha; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D054645:Protein Phosphatase 1