Universität zu Köln

Mueller, Kristina M., Kornfeld, Jan-Wilhelm ORCID: 0000-0002-6802-4442, Friedbichler, Katrin, Blaas, Leander ORCID: 0000-0002-7822-697X, Egger, Gerda ORCID: 0000-0003-2489-155X, Esterbauer, Harald, Hasselblatt, Peter, Schlederer, Michaela, Haindl, Susanne, Wagner, Kay-Uwe ORCID: 0000-0002-5081-0226, Engblom, David, Haemmerle, Guenter ORCID: 0000-0001-9900-5896, Kratky, Dagmar ORCID: 0000-0003-1357-7573, Sexl, Veronika ORCID: 0000-0001-9363-0412, Kenner, Lukas ORCID: 0000-0003-2184-1338, Kozlov, Andrey V., Terracciano, Luigi, Zechner, Rudolf ORCID: 0000-0001-5483-1182, Schuetz, Guenther, Casanova, Emilio ORCID: 0000-0001-7992-5361, Pospisilik, J. Andrew, Heim, Markus H. and Moriggl, Richard ORCID: 0000-0003-0918-9463 (2011). Impairment of Hepatic Growth Hormone and Glucocorticoid Receptor Signaling Causes Steatosis and Hepatocellular Carcinoma in Mice. Hepatology, 54 (4). S. 1398 - 1410. HOBOKEN: WILEY. ISSN 1527-3350

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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)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mueller, Kristina M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kornfeld, Jan-Wilhelm UNSPECIFIED orcid.org/0000-0002-6802-4442 UNSPECIFIED Friedbichler, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Blaas, Leander UNSPECIFIED orcid.org/0000-0002-7822-697X UNSPECIFIED Egger, Gerda UNSPECIFIED orcid.org/0000-0003-2489-155X UNSPECIFIED Esterbauer, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Hasselblatt, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlederer, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Haindl, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagner, Kay-Uwe UNSPECIFIED orcid.org/0000-0002-5081-0226 UNSPECIFIED Engblom, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Haemmerle, Guenter UNSPECIFIED orcid.org/0000-0001-9900-5896 UNSPECIFIED Kratky, Dagmar UNSPECIFIED orcid.org/0000-0003-1357-7573 UNSPECIFIED Sexl, Veronika UNSPECIFIED orcid.org/0000-0001-9363-0412 UNSPECIFIED Kenner, Lukas UNSPECIFIED orcid.org/0000-0003-2184-1338 UNSPECIFIED Kozlov, Andrey V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Terracciano, Luigi UNSPECIFIED UNSPECIFIED UNSPECIFIED Zechner, Rudolf UNSPECIFIED orcid.org/0000-0001-5483-1182 UNSPECIFIED Schuetz, Guenther UNSPECIFIED UNSPECIFIED UNSPECIFIED Casanova, Emilio UNSPECIFIED orcid.org/0000-0001-7992-5361 UNSPECIFIED Pospisilik, J. Andrew UNSPECIFIED UNSPECIFIED UNSPECIFIED Heim, Markus H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moriggl, Richard UNSPECIFIED orcid.org/0000-0003-0918-9463 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-488445
DOI:	10.1002/hep.24509
Journal or Publication Title:	Hepatology
Volume:	54
Number:	4
Page Range:	S. 1398 - 1410
Date:	2011
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1527-3350
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FATTY LIVER-DISEASE; CORTICOSTEROID-BINDING GLOBULIN; INSULIN-RESISTANCE; STEATOHEPATITIS; TRANSCRIPTION; ACTIVATION; FIBROSIS; STAT5B; INFLAMMATION; HEPATOCYTES Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48844