Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Stiedl, P; McMahon, R; Blaas, L; Stanek, V; Svinka, J; Grabner, B; Zollner, G; Kessler, SM; Claudel, T; Müller, M; Mikulits, W; Bilban, M; Esterbauer, H; Eferl, R; Haybaeck, J; Trauner, M; Casanova, E.
Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis.
Hepatology. 2015; 61(2):613-626
Doi: 10.1002/hep.27408
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- Co-Autor*innen der Med Uni Graz
- Claudel Thierry
- Haybäck Johannes
- Kessler Sonja
- Müller Michaela
- Trauner Michael
- Zollner Gernot
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- Abstract:
- Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the GH receptor gene (Ghr(-/-), a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2(-/-)), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr(-/-);Mdr2(-/-) mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation, and increased collagen deposition relative to Mdr2(-/-) mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr(-/-);Mdr2(-/-) mice had a pronounced down-regulation of hepatoprotective genes Hnf6, Egfr, and Igf-1, and significantly increased levels of reactive oxygen species (ROS) and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr(-/-)) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis, and bile infarcts compared to their wild-type littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr(-/-);Mdr2(-/-) mice displayed a significant decrease in tumor incidence compared to Mdr2(-/-) mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver. GH resistance dramatically exacerbates liver fibrosis in a mouse model of inflammatory cholestasis, therefore suggesting that GH resistance plays a causal role in the disease and provides a novel target for the development of liver fibrosis treatments. © 2014 by the American Association for the Study of Liver Diseases.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Bile Acids and Salts - metabolism
- Cholestasis - complications
- Growth Hormone - metabolism
- Hepatocytes - physiology
- Homeostasis -
- Liver Cirrhosis - etiology Liver Cirrhosis - metabolism
- Liver Neoplasms, Experimental - etiology
- Male -
- Mice -
- Mice, Inbred C57BL -
- Mice, Knockout -
- P-Glycoproteins - genetics
- Phenotype -
- Reactive Oxygen Species - metabolism
- Receptors, Somatotropin - genetics
- Up-Regulation -