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

TY - JOUR

T1 - Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.

AU - Mueller, Kristina M

AU - Kornfeld, Jan

AU - Friedbichler, Katrin

AU - Blaas, Leander

AU - Egger, Gerda

AU - Esterbauer, Harald

AU - Hasselblatt, Peter

AU - Schlederer, Michaela

AU - Haindl, Susanne

AU - Wagner, Kay-Uwe

AU - Engblom, David

AU - Haemmerle, Guenter

AU - Kratky, Dagmar

AU - Sexl, Veronika

AU - Kenner, Lukas

AU - Kozlov, Andrey V

AU - Terracciano, Luigi

AU - Zechner, Rudolf

AU - Schuetz, Guenther

AU - Casanova, Emilio

AU - Pospisilik, J Andrew

AU - Heim, Markus H

AU - Moriggl, Richard

PY - 2011

Y1 - 2011

N2 - 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-?) 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-?) 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.

AB - 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-?) 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-?) 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.

KW - Animals

KW - Male

KW - Immunohistochemistry

KW - Risk Assessment

KW - Disease Models, Animal

KW - Mice

KW - Mice, Knockout

KW - Signal Transduction

KW - Blotting, Western

KW - Analysis of Variance

KW - Reference Values

KW - Random Allocation

KW - Tissue Culture Techniques

KW - Carcinoma, Hepatocellular/metabolism/pathology

KW - Fatty Liver/metabolism/pathology

KW - Growth Hormone/metabolism

KW - Lipodystrophy/metabolism/pathology

KW - Liver Neoplasms/metabolism/pathology

KW - Receptors, Glucocorticoid/genetics/metabolism

KW - STAT5 Transcription Factor/metabolism

KW - Animals

KW - Male

KW - Immunohistochemistry

KW - Risk Assessment

KW - Disease Models, Animal

KW - Mice

KW - Mice, Knockout

KW - Signal Transduction

KW - Blotting, Western

KW - Analysis of Variance

KW - Reference Values

KW - Random Allocation

KW - Tissue Culture Techniques

KW - Carcinoma, Hepatocellular/metabolism/pathology

KW - Fatty Liver/metabolism/pathology

KW - Growth Hormone/metabolism

KW - Lipodystrophy/metabolism/pathology

KW - Liver Neoplasms/metabolism/pathology

KW - Receptors, Glucocorticoid/genetics/metabolism

KW - STAT5 Transcription Factor/metabolism

M3 - SCORING: Journal article

VL - 54

SP - 1398

EP - 1409

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 4

M1 - 4

ER -