Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling
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 protect...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-08-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713003859 |
| _version_ | 1811317170296061952 |
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| author | 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 F. Thomas Wunderlich |
| author_facet | 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 F. Thomas Wunderlich |
| author_sort | Sabine Gruber |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T12:02:12Z |
| format | Article |
| id | doaj.art-f7eb9bd33a6f47508fe9e6aae7823951 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T12:02:12Z |
| publishDate | 2013-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f7eb9bd33a6f47508fe9e6aae78239512022-12-22T02:47:44ZengElsevierCell Reports2211-12472013-08-014466968010.1016/j.celrep.2013.07.023Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα SignalingSabine Gruber0Beate K. Straub1P. Justus Ackermann2Claudia M. Wunderlich3Jan Mauer4Jens M. Seeger5Hildegard Büning6Lukas Heukamp7Hamid Kashkar8Peter Schirmacher9Jens C. Brüning10F. Thomas Wunderlich11Max Planck Institute for Neurological Research Cologne; Institute for Genetics, University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD); Center for Molecular Medicine Cologne (CMMC); Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931 Cologne, GermanyInstitute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, GermanyMax Planck Institute for Neurological Research Cologne; Institute for Genetics, University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD); Center for Molecular Medicine Cologne (CMMC); Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931 Cologne, GermanyMax Planck Institute for Neurological Research Cologne; Institute for Genetics, University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD); Center for Molecular Medicine Cologne (CMMC); Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931 Cologne, GermanyMax Planck Institute for Neurological Research Cologne; Institute for Genetics, University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD); Center for Molecular Medicine Cologne (CMMC); Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931 Cologne, GermanyInstitute for Medical Microbiology, Immunology and Hygiene, University of Cologne; CMMC; CECAD; 50937 Cologne, GermanyDepartment I of Internal Medicine, University of Cologne; CMMC; 50935 Cologne, GermanyInstitute of Pathology, University of Cologne, 50937 Cologne, GermanyInstitute for Medical Microbiology, Immunology and Hygiene, University of Cologne; CMMC; CECAD; 50937 Cologne, GermanyInstitute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, GermanyMax Planck Institute for Neurological Research Cologne; Institute for Genetics, University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD); Center for Molecular Medicine Cologne (CMMC); Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931 Cologne, GermanyMax Planck Institute for Neurological Research Cologne; Institute for Genetics, University of Cologne; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD); Center for Molecular Medicine Cologne (CMMC); Center for Endocrinology, Diabetes and Preventive Medicine (CEDP) Cologne, 50931 Cologne, GermanyObesity 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.http://www.sciencedirect.com/science/article/pii/S2211124713003859 |
| spellingShingle | 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 F. Thomas Wunderlich Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling Cell Reports |
| title | Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling |
| title_full | Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling |
| title_fullStr | Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling |
| title_full_unstemmed | Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling |
| title_short | Obesity Promotes Liver Carcinogenesis via Mcl-1 Stabilization Independent of IL-6Rα Signaling |
| title_sort | obesity promotes liver carcinogenesis via mcl 1 stabilization independent of il 6rα signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713003859 |
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