Title |
Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis
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Published in |
Journal of Molecular Medicine, August 2016
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DOI | 10.1007/s00109-016-1462-8 |
Pubmed ID | |
Authors |
Jasmin Svinka, Sandra Pflügler, Markus Mair, Hanns-Ulrich Marschall, Jan G. Hengstler, Patricia Stiedl, Valeria Poli, Emilio Casanova, Gerald Timelthaler, Maria Sibilia, Robert Eferl |
Abstract |
We have demonstrated that the signal transducer and activator of transcription 3 (STAT3) protects from cholestatic liver injury. Specific ablation of STAT3 in hepatocytes and cholangiocytes (STAT3(∆hc)) aggravated liver damage and fibrosis in the Mdr2(-/-) (multidrug resistance 2) mouse model for cholestatic disease. Upregulation of bile acid biosynthesis genes and downregulation of epidermal growth factor receptor (EGFR) expression were observed in STAT3(∆hc) Mdr2(-/-) mice but the functional consequences of these processes in cholestatic liver injury remained unclear. Here, we show normal canalicular architecture and bile flow but increased amounts of bile acids in the bile of STAT3(∆hc) Mdr2(-/-) mice. Moreover, STAT3-deficient hepatocytes displayed increased sensitivity to bile acid-induced apoptosis in vitro. Since EGFR signaling has been reported to protect hepatocytes from bile acid-induced apoptosis, we generated mice with hepatocyte/cholangiocyte-specific ablation of EGFR (EGFR(∆hc)) and crossed them to Mdr2(-/-) mice. Importantly, deletion of EGFR phenocopied deletion of STAT3 and led to aggravated liver damage, liver fibrosis, and hyperproliferation of K19(+) cholangiocytes. Our data demonstrate hepatoprotective functions of the STAT3-EGFR signaling axis in cholestatic liver disease. STAT3 is a negative regulator of bile acid biosynthesis. STAT3 protects from bile acid-induced apoptosis and regulates EGFR expression. EGFR signaling protects from cholestatic liver injury and fibrosis. |
X Demographics
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Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 25 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 3 | 12% |
Professor > Associate Professor | 3 | 12% |
Student > Ph. D. Student | 3 | 12% |
Unspecified | 2 | 8% |
Other | 2 | 8% |
Other | 2 | 8% |
Unknown | 10 | 40% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 5 | 20% |
Unspecified | 2 | 8% |
Agricultural and Biological Sciences | 2 | 8% |
Immunology and Microbiology | 1 | 4% |
Medicine and Dentistry | 1 | 4% |
Other | 2 | 8% |
Unknown | 12 | 48% |