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Impairment of Hepat...
Impairment of Hepatic Growth Hormone and Glucocorticoid Receptor Signaling Causes Steatosis and Hepatocellular Carcinoma in Mice
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- Mueller, Kristina M (författare)
- Ludwig Boltzmann Institute for Cancer Research
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- Kornfeld, Jan-Wilhelm (författare)
- University of Cologne
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- Friedbichler, Katrin (författare)
- Ludwig Boltzmann Institute for Cancer Research
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- Blaas, Leander (författare)
- Karolinska Institutet,Ludwig Boltzmann Institute for Cancer Research
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- Egger, Gerda (författare)
- Medical University of Vienna
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- Esterbauer, Harald (författare)
- Medical University of Vienna
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- Hasselblatt, Peter (författare)
- Freiburg University Hospital
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- Schlederer, Michaela (författare)
- Ludwig Boltzmann Institute for Cancer Research
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- Haindl, Susanne (författare)
- Ludwig Boltzmann Institute for Cancer Research
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- Wagner, Kay-Uwe (författare)
- University of Nebraska Medical Centre
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- Engblom, David (författare)
- Linköpings universitet,Cellbiologi,Hälsouniversitetet
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- Haemmerle, Guenter (författare)
- Institute for Molecular Bioscience, Graz
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- Kratky, Dagmar (författare)
- Medical University of Graz
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- Sexl, Veronika (författare)
- Vet University of Vienna
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- Kenner, Lukas (författare)
- Ludwig Boltzmann Institute for Cancer Research
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- Kozlov, Andrey V (författare)
- Ludwig Boltzmann Institute for Cancer Research
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- Terracciano, Luigi (författare)
- University of Basel Hospital
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- Zechner, Rudolf (författare)
- Institute for Molecular Bioscience, Graz
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- Schuetz, Guenther (författare)
- German Cancer Research Centre
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- Casanova, Emilio (författare)
- Ludwig Boltzmann Institute for Cancer Research
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- Pospisilik, J Andrew (författare)
- Max Planck Institute Immunobiology
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- Heim, Markus H (författare)
- University of Basel Hospital
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- Moriggl, Richard (författare)
- Ludwig Boltzmann Institute for Cancer Research
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(creator_code:org_t)
- 2011-09-27
- 2011
- Engelska.
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Ingår i: Hepatology. - : Wiley-Blackwell. - 0270-9139 .- 1527-3350. ; 54:4, s. 1398-1409
- Relaterad länk:
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https://aasldpubs.on...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Growth hormone (GH)-activated signal transducer and activator of transcription 5 (STAT5) and the glucocorticoid (GC)-responsive glucocorticoid receptor (GR) are important signal integrators in the liver during metabolic and physiologic stress. Their deregulation has been implicated in the development of metabolic liver diseases, such as steatosis and progression to fibrosis. Using liver-specific STAT5 and GR knockout mice, we addressed their role in metabolism and liver cancer onset. STAT5 single and STAT5/GR double mutants developed steatosis, but only double-mutant mice progressed to liver cancer. Mechanistically, STAT5 deficiency led to the up-regulation of prolipogenic sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator activated receptor gamma (PPAR-gamma) signaling. Combined loss of STAT5/GR resulted in GH resistance and hypercortisolism. The combination of both induced expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver, thereby aggravating STAT5-dependent steatosis. The metabolic dysfunctions in STAT5/GR compound knockout animals led to the development of hepatic dysplasia at 9 months of age. At 12 months, 35% of STAT5/GR-deficient livers harbored dysplastic nodules and similar to 60% hepatocellular carcinomas (HCCs). HCC development was associated with GH and insulin resistance, enhanced tumor necrosis factor alpha (TNF-alpha) expression, high reactive oxygen species levels, and augmented liver and DNA damage parameters. Moreover, activation of the c-Jun N-terminal kinase 1 (JNK1) and STAT3 was prominent. Conclusion: Hepatic STAT5/GR signaling is crucial for the maintenance of systemic lipid homeostasis. Impairment of both signaling cascades causes severe metabolic liver disease and promotes spontaneous hepatic tumorigenesis.
Nyckelord
- MEDICINE
- MEDICIN
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- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Mueller, Kristin ...
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Kornfeld, Jan-Wi ...
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Friedbichler, Ka ...
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Blaas, Leander
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Egger, Gerda
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Esterbauer, Hara ...
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visa fler...
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Hasselblatt, Pet ...
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Schlederer, Mich ...
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Haindl, Susanne
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Wagner, Kay-Uwe
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Engblom, David
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Haemmerle, Guent ...
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Kratky, Dagmar
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Sexl, Veronika
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Kenner, Lukas
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Kozlov, Andrey V
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Terracciano, Lui ...
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Zechner, Rudolf
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Schuetz, Guenthe ...
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Casanova, Emilio
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Pospisilik, J An ...
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Heim, Markus H
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Moriggl, Richard
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- Artiklar i publikationen
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Hepatology
- Av lärosätet
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Linköpings universitet
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Karolinska Institutet