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

被引：54

作者：

Blaas, Leander ^{[1
]}

Kornfeld, Jan-Wilhelm ^{[1
]}

Schramek, Daniel ^{[2
]}

Musteanu, Monica ^{[1
]}

Zollner, Gernot ^{[3
]}

Gumhold, Judith ^{[3
]}

van Zijl, Franziska ^{[4
]}

Schneller, Doris ^{[4
]}

Esterbauer, Harald ^{[5
]}

Egger, Gerda ^{[6
]}

Mair, Markus ^{[1
]}

Kenner, Lukas ^{[1
,6
]}

Mikulits, Wolfgang ^{[4
]}

Eferl, Robert ^{[1
]}

Moriggl, Richard ^{[1
]}

Penninger, Josef ^{[2
]}

Trauner, Michael ^{[3
]}

Casanova, Emilio ^{[1
]}

机构：

[1] LBICR, Vienna, Austria

[2] Austrian Acad Sci IMBA, Inst Mol Biol, Vienna, Austria

[3] Med Univ Graz, Dept Internal Med, Div Gastroenterol & Hepatol, Lab Expt & Mol Hepatol, Graz, Austria

[4] Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria

[5] Med Univ Vienna, Dept Med & Chem Lab Diagnost, Vienna, Austria

[6] Med Univ Vienna, Clin Inst Pathol, Vienna, Austria

来源：

HEPATOLOGY | 2010年 / 51卷 / 04期

基金：

奥地利科学基金会;

关键词：

BILE-ACID; FACTOR-I; INDUCED APOPTOSIS; GENE; RECEPTOR; STAT5; EXPRESSION; PROLIFERATION; REGENERATION; HEPATOCYTES;

D O I：

10.1002/hep.23469

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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 (Lift) 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. (HEPATOLOGY 2010;51:1319-1326.)

引用

页码：1319 / 1326

页数：8

共 45 条

[1]

Growth hormone-stimulated IGF-1 generation in cirrhosis reflects hepatocellular dysfunction [J].