Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

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.
Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.
Hepatology. 2011; 54(4):1398-1409 Doi: 10.1002/hep.24509 [OPEN ACCESS]
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Co-authors Med Uni Graz

Kratky Dagmar

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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-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. (HEPATOLOGY 2011;54:1398-1409)

Find related publications in this database (using NLM MeSH Indexing)

Analysis of Variance -

Animals -

Blotting, Western -

Carcinoma, Hepatocellular - metabolism

Disease Models, Animal -

Fatty Liver - metabolism

Growth Hormone - metabolism

Immunohistochemistry -

Lipodystrophy - metabolism

Liver Neoplasms - metabolism

Male -

Mice -

Mice, Knockout -

Random Allocation -

Receptors, Glucocorticoid - genetics

Reference Values -

Risk Assessment -

STAT5 Transcription Factor - metabolism

Signal Transduction -

Tissue Culture Techniques -

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