title: Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis.
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∆hcMdr2-/-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∆hcMdr2-/-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.
authors: Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.
authors: Jasmin
authors: J
authors: Svinka
authors: Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.
authors: Sandra
authors: S
authors: Pflügler
authors: Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
authors: Markus
authors: M
authors: Mair
authors: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors: Hanns-Ulrich
authors: HU
authors: Marschall
authors: Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo), Dortmund, Germany.
authors: Jan G
authors: JG
authors: Hengstler
authors: Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
authors: Patricia
authors: P
authors: Stiedl
authors: Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.
authors: Valeria
authors: V
authors: Poli
authors: Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.|Department of Pharmacology, Center of Physiology and Pharmacology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors: Emilio
authors: E
authors: Casanova
authors: Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.
authors: Gerald
authors: G
authors: Timelthaler
authors: Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.
authors: Maria
authors: M
authors: Sibilia
authors: Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria. robert.eferl@meduniwien.ac.at.
authors: Robert
authors: R
authors: Eferl
mesh_terms: D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000096:biosynthesis; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; D050796:STAT3 Transcription Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D053148:Caspase 3; D053181:Caspase 8
keywords: Bile acids; Cholestasis; Epidermal growth factor receptor EGFR; Hepatocyte apoptosis; Liver injury; Signal transducer and activator of transcription 3 STAT3