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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Blaas, L; Kornfeld, JW; Schramek, D; Musteanu, M; Zollner, G; Gumhold, J; van Zijl, F; Schneller, D; Esterbauer, H; Egger, G; Mair, M; Kenner, L; Mikulits, W; Eferl, R; Moriggl, R; Penninger, J; Trauner, M; Casanova, E.
Disruption of the growth hormone--signal transducer and activator of transcription 5--insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis.
Hepatology. 2010; 51(4):1319-1326
Doi: 10.1002/hep.23469
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- Co-Autor*innen der Med Uni Graz
- Sommer Judith
- Trauner Michael
- Zollner Gernot
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- Abstract:
- Growth hormone (GH) resistance and low serum levels of insulinlike growth factor 1 (IGF-1) are common features in human liver fibrosis and cirrhosis. Signal transducer and activator of transcription 5 (STAT5) controls several vital functions in the liver, including GH-mediated transcription of IGF-1. To investigate the role of STAT5 in liver fibrogenesis, we specifically deleted the Stat5a/b locus both in hepatocytes and cholangiocytes in the multidrug resistance gene 2 knockout (Mdr2(-/-)) mouse model of cholestasis. Double knockout mice develop an early and severe liver fibrosis phenotype, accompanied by perturbed expression of key regulators of bile acid homeostasis. Deletion of Stat5 resulted in GH resistance, and IGF-1 levels in serum were undetectable. We could observe reduced expression of important hepatoprotective genes, such as epidermal growth factor receptor (Egfr), hepatocyte nuclear factor 6 (Hnf6), prolactin receptor (Prlr), and leukemia inhibitory factor receptor (Lifr) as well as increased numbers of apoptotic hepatocytes. Our data suggest that loss of STAT5 sensitizes hepatocytes to bile acid-induced damage and apoptosis caused by disruption of GH-induced transcription of Igf-1 and down-regulation of hepatoprotective genes. These findings could contribute to the understanding of liver fibrosis and future treatment strategies for liver fibrosis.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apoptosis -
- Cholestasis - complications
- Disease Models, Animal -
- Growth Hormone - physiology
- Hepatocyte Nuclear Factor 6 - genetics
- Insulin-Like Growth Factor I - physiology
- Liver Cirrhosis, Experimental - etiology
- Male -
- Mice -
- Mice, Inbred C57BL -
- Mice, Knockout -
- P-Glycoproteins - physiology
- Phenotype -
- Receptor, Epidermal Growth Factor - genetics
- STAT5 Transcription Factor - physiology
- Signal Transduction -