Epidermal growth factor signaling protects from cholestatic liver injury and fibrosisReportar como inadecuado

Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Journal of Molecular Medicine

, Volume 95, Issue 1, pp 109–117

First Online: 27 August 2016Received: 24 June 2016Revised: 08 August 2016Accepted: 12 August 2016

AbstractWe 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 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 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 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 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.

Key messageSTAT3 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.

KeywordsEpidermal growth factor receptor EGFR Signal transducer and activator of transcription 3 STAT3 Cholestasis Bile acids Liver injury Hepatocyte apoptosis  Download fulltext PDF

Autor: Jasmin Svinka - Sandra Pflügler - Markus Mair - Hanns-Ulrich Marschall - Jan G. Hengstler - Patricia Stiedl - Valeria Pol

Fuente: https://link.springer.com/

Documentos relacionados