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Impairment of Hepatic Growth Hormone and Glucocorticoid Receptor Signaling Causes Steatosis and Hepatocellular Carcinoma in Mice
Ludwig Boltzmann Institute for Cancer Research.
University of Cologne.
Ludwig Boltzmann Institute for Cancer Research.
Ludwig Boltzmann Institute for Cancer Research.
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2011 (English)In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 54, no 4, 1398-1409 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell , 2011. Vol. 54, no 4, 1398-1409 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-71643DOI: 10.1002/hep.24509ISI: 000295577200032OAI: diva2:451821
Funding Agencies|Austrian Science Funds (FWF)|SFB F28|FWF|SFB F30|Elise Richter fellowship (FWF)|V102-B12|grant GEN-AU Austromouse||Vienna Science and Technology Fund|LS07-058|JDRF||Available from: 2011-10-27 Created: 2011-10-27 Last updated: 2011-10-27

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