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

Kristina M. Mueller, Jan Wilhelm Kornfeld, Katrin Friedbichler, Leander Blaas, Gerda Egger, Harald Esterbauer, Peter Hasselblatt, Michaela Schlederer, Susanne Haindl, Kay-Uwe Wagner, David Engblom, Guenter Haemmerle, Dagmar Kratky, Veronika Sexl, Lukas Kenner, Andrey V. Kozlov, Luigi Terracciano, Rudolf Zechner, Guenther Schuetz, Emilio Casanova & 3 others J. Andrew Pospisilik, Markus H. Heim, Richard Moriggl

Research output: Contribution to journalArticle

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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-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. 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.

Original languageEnglish (US)
Pages (from-to)1398-1409
Number of pages12
JournalHepatology
Volume54
Issue number4
DOIs
StatePublished - Oct 1 2011

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STAT5 Transcription Factor
Somatotropin Receptors
Glucocorticoid Receptors
Hepatocellular Carcinoma
Liver
Growth Hormone
Metabolic Diseases
Liver Neoplasms
Adipose Tissue
Liver Diseases
Mitogen-Activated Protein Kinase 8
Lipid Mobilization
Sterol Regulatory Element Binding Protein 1
Lipids
Peroxisome Proliferator-Activated Receptors
Cushing Syndrome
PPAR gamma
Lipase
Knockout Mice
Glucocorticoids

ASJC Scopus subject areas

  • Hepatology

Cite this

Mueller, K. M., Kornfeld, J. W., Friedbichler, K., Blaas, L., Egger, G., Esterbauer, H., ... Moriggl, R. (2011). Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology, 54(4), 1398-1409. https://doi.org/10.1002/hep.24509

Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. / Mueller, Kristina M.; Kornfeld, Jan Wilhelm; Friedbichler, Katrin; Blaas, Leander; Egger, Gerda; Esterbauer, Harald; Hasselblatt, Peter; Schlederer, Michaela; Haindl, Susanne; Wagner, Kay-Uwe; Engblom, David; Haemmerle, Guenter; Kratky, Dagmar; Sexl, Veronika; Kenner, Lukas; Kozlov, Andrey V.; Terracciano, Luigi; Zechner, Rudolf; Schuetz, Guenther; Casanova, Emilio; Pospisilik, J. Andrew; Heim, Markus H.; Moriggl, Richard.

In: Hepatology, Vol. 54, No. 4, 01.10.2011, p. 1398-1409.

Research output: Contribution to journalArticle

Mueller, KM, Kornfeld, JW, Friedbichler, K, Blaas, L, Egger, G, Esterbauer, H, Hasselblatt, P, Schlederer, M, Haindl, S, Wagner, K-U, 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 2011, 'Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice', Hepatology, vol. 54, no. 4, pp. 1398-1409. https://doi.org/10.1002/hep.24509
Mueller, Kristina M. ; Kornfeld, Jan Wilhelm ; Friedbichler, Katrin ; Blaas, Leander ; Egger, Gerda ; Esterbauer, Harald ; Hasselblatt, Peter ; Schlederer, Michaela ; Haindl, Susanne ; Wagner, Kay-Uwe ; Engblom, David ; Haemmerle, Guenter ; Kratky, Dagmar ; Sexl, Veronika ; Kenner, Lukas ; Kozlov, Andrey V. ; Terracciano, Luigi ; Zechner, Rudolf ; Schuetz, Guenther ; Casanova, Emilio ; Pospisilik, J. Andrew ; Heim, Markus H. ; Moriggl, Richard. / Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. In: Hepatology. 2011 ; Vol. 54, No. 4. pp. 1398-1409.
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AU - Mueller, Kristina M.

AU - Kornfeld, Jan Wilhelm

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 - 2011/10/1

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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-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. 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.

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