title: Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice.
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.
  
  
  CONCLUSIONS
  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.
authors: Ludwig-Boltzmann-Institute for Cancer Research, Vienna, Austria.
authors: Kristina M
authors: KM
authors: Mueller
authors: Jan-Wilhelm
authors: JW
authors: Kornfeld
authors: Katrin
authors: K
authors: Friedbichler
authors: Leander
authors: L
authors: Blaas
authors: Gerda
authors: G
authors: Egger
authors: Harald
authors: H
authors: Esterbauer
authors: Peter
authors: P
authors: Hasselblatt
authors: Michaela
authors: M
authors: Schlederer
authors: Susanne
authors: S
authors: Haindl
authors: Kay-Uwe
authors: KU
authors: Wagner
authors: David
authors: D
authors: Engblom
authors: Guenter
authors: G
authors: Haemmerle
authors: Dagmar
authors: D
authors: Kratky
authors: Veronika
authors: V
authors: Sexl
authors: Lukas
authors: L
authors: Kenner
authors: Andrey V
authors: AV
authors: Kozlov
authors: Luigi
authors: L
authors: Terracciano
authors: Rudolf
authors: R
authors: Zechner
authors: Guenther
authors: G
authors: Schuetz
authors: Emilio
authors: E
authors: Casanova
authors: J Andrew
authors: JA
authors: Pospisilik
authors: Markus H
authors: MH
authors: Heim
authors: Richard
authors: R
authors: Moriggl
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D013006:Growth Hormone / Q000378:metabolism*; D007150:Immunohistochemistry; D008060:Lipodystrophy / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D018570:Risk Assessment; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D011965:Receptors, Glucocorticoid; D050799:STAT5 Transcription Factor; D013006:Growth Hormone