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Type of publication: Journal Article
Type of document: Full Paper

Year: 2011

Authors: Mueller, KM; Kornfeld, JW; Friedbichler, K; Blaas, L; Egger, G; Esterbauer, H; Hasselblatt, P; Schlederer, M; Haindl, S; Wagner, KU; Engblom, D; Haemmerle, G; Kratky, D; Sexl, V; Kenner, L; Kozlov, AV; Terracciano, L; Zechner, R; Schuetz, G; Casanova, E; Pospisilik, JA; Heim, MH; Moriggl, R

Title: Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.

Source: Hepatology. 2011; 54(4):1398-1409



Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Müller Kristina
Sexl Veronika

Vetmed Research Units
Institute of Pharmacology and Toxicology


Abstract:
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-γ) 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 ∼ 60% hepatocellular carcinomas (HCCs). HCC development was associated with GH and insulin resistance, enhanced tumor necrosis factor alpha (TNF-α) 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.

Keywords Pubmed: Analysis of Variance
Animals
Blotting, Western
Carcinoma, Hepatocellular/metabolism*
Carcinoma, Hepatocellular/pathology
Disease Models, Animal
Fatty Liver/metabolism*
Fatty Liver/pathology
Growth Hormone/metabolism*
Immunohistochemistry
Lipodystrophy/metabolism
Lipodystrophy/pathology
Liver Neoplasms/metabolism*
Liver Neoplasms/pathology
Male
Mice
Mice, Knockout
Random Allocation
Receptors, Glucocorticoid/genetics
Receptors, Glucocorticoid/metabolism*
Reference Values
Risk Assessment
STAT5 Transcription Factor/metabolism*
Signal Transduction
Tissue Culture Techniques


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