These authors contributed equally to this work.
Article first published online: 27 SEP 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 4, pages 1398–1409, October 2011
How to Cite
Mueller, K. M., Kornfeld, J.-W., 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, A. V., Terracciano, L., Zechner, R., Schuetz, G., Casanova, E., Pospisilik, J. A., Heim, M. H. and Moriggl, R. (2011), Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Hepatology, 54: 1398–1409. doi: 10.1002/hep.24509
Potential conflict of interest: Nothing to report.
This work was supported by grant SFB F28 from the Austrian Science Funds (FWF; to R.M., J.W.K., K.M.M., V.S., and K.F.) and grant SFB F30 (FWF; to G.H., D.K., and R.Z.). G.E. was supported by an Elise Richter fellowship (FWF; V102-B12). L.B. and E.C. were supported by grant GEN-AU Austromouse. H.E. and J.A.P. were supported by grants of the Vienna Science and Technology Fund (WWTF project LS07-058) and JDRF.
Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms
- Issue published online: 27 SEP 2011
- Article first published online: 27 SEP 2011
- Accepted manuscript online: 2 JUL 2011 03:33PM EST
- Manuscript Accepted: 15 JUN 2011
- Manuscript Received: 15 MAR 2011
- Unknown funding agency
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. (HEPATOLOGY 2011;54:1398–1409)