Disruption of the growth hormone--signal transducer and activator of transcription 5--insulinlike growth factor 1 axis severely aggravates liver fibrosis in a mouse model of cholestasis.
Growth hormone (GH) resistance and low serum levels of insulinlike growth factor 1 (IGF-1) are common features in human liver fibrosis and cirrhosis. Signal transducer and activator of transcription 5 (STAT5) controls several vital functions in the liver, including GH-mediated transcription of IGF-1. To investigate the role of STAT5 in liver fibrogenesis, we specifically deleted the Stat5a/b locus both in hepatocytes and cholangiocytes in the multidrug resistance gene 2 knockout (Mdr2(-/-)) mouse model of cholestasis. Double knockout mice develop an early and severe liver fibrosis phenotype, accompanied by perturbed expression of key regulators of bile acid homeostasis. Deletion of Stat5 resulted in GH resistance, and IGF-1 levels in serum were undetectable. We could observe reduced expression of important hepatoprotective genes, such as epidermal growth factor receptor (Egfr), hepatocyte nuclear factor 6 (Hnf6), prolactin receptor (Prlr), and leukemia inhibitory factor receptor (Lifr) as well as increased numbers of apoptotic hepatocytes.


CONCLUSIONS
Our data suggest that loss of STAT5 sensitizes hepatocytes to bile acid-induced damage and apoptosis caused by disruption of GH-induced transcription of Igf-1 and down-regulation of hepatoprotective genes. These findings could contribute to the understanding of liver fibrosis and future treatment strategies for liver fibrosis.
Blaas
Leander
L
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Kornfeld
Jan-Wilhelm
JW
Schramek
Daniel
D
Musteanu
Monica
M
Zollner
Gernot
G
Gumhold
Judith
J
van Zijl
Franziska
F
Schneller
Doris
D
Esterbauer
Harald
H
Egger
Gerda
G
Mair
Markus
M
Kenner
Lukas
L
Mikulits
Wolfgang
W
Eferl
Robert
R
Moriggl
Richard
R
Penninger
Josef
J
Trauner
Michael
M
Casanova
Emilio
E
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002779:Cholestasis / Q000150:complications*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics; D013006:Growth Hormone / Q000502:physiology*; D051559:Hepatocyte Nuclear Factor 6 / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D066246:ErbB Receptors; D013006:Growth Hormone; D051559:Hepatocyte Nuclear Factor 6; D007334:Insulin-Like Growth Factor I; D050799:STAT5 Transcription Factor; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C496606:Onecut1 protein, mouse; C494093:Stat5a protein, mouse