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SHR Neuro Krebs Kardio Lipid

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 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG


Autor/innen der Med Uni Graz:
Claudel Thierry
Haybäck Johannes
Kessler Sonja
Müller Michaela
Trauner Michael
Zollner Gernot

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Number of Figures: 7
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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 -

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