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

Leander Blaas, Jan-Wilhelm Kornfeld, Daniel Schramek, Monica Musteanu, Gernot Zollner, Judith Gumhold, Franziska van Zijl, Doris Schneller, Harald Esterbauer, Gerda Egger, Markus Mair, Lukas Kenner, Wolfgang Mikulits, Robert Eferl, Richard Moriggl, Josef Penninger, Michael Trauner, Emilio Casanova

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstract

UNLABELLED: 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.

CONCLUSION: 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.

OriginalsprogEngelsk
TidsskriftHepatology (Baltimore, Md.)
Vol/bind51
Udgave nummer4
Sider (fra-til)1319-1326
ISSN0270-9139
DOI
StatusUdgivet - apr. 2010
Udgivet eksterntJa

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