Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis

Jasmin Svinka,Valeria Poli,Markus Mair,Hanns-Ulrich Marschall,Patricia Stiedl,Maria Sibilia,Jan G Hengstler,Robert Eferl,Sandra Pflügler,Emilio Casanova,Gerald Timelthaler

doi:10.1007/s00109-016-1462-8

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.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.

Highlights

Chronic cholestatic liver diseases are characterized by retention of bile acids in the liver which results in alterations of hepatobiliary bile acid transport and enzyme activities participating in bile acid biosynthesis
We demonstrated that enzymes for bile acid biosynthesis are upregulated in livers of Mdr2−/− mice, lacking signal transducer and activator of transcription 3 (STAT3) in hepatocytes and cholangiocytes (STAT3Δhc) [6], which might result in increased production of toxic bile and aggravated cholestatic liver damage
We have recently shown that STAT3 is a negative regulator of bile acid biosynthesis gene expression [6]

Summary

Introduction

Chronic cholestatic liver diseases are characterized by retention of bile acids in the liver which results in alterations of hepatobiliary bile acid transport and enzyme activities participating in bile acid biosynthesis. Deposition of collagen and other extracellular matrix components is an orchestrated event in cholestatic liver fibrosis and involves several cell types including Kupffer cells and stellate cells. Despite profound knowledge about cell types that promote cholestatic liver fibrosis and cirrhosis, little is known about hepatoprotective factors that modulate initial events of cholestatic liver injury. The transcription factor STAT3 is required for liver regeneration and hepatoprotection in various chronic liver diseases [4]. STAT3 is mainly activated by IL-6 (interleukin 6) and IL-22 in hepatocytes. These cytokines bind to gp130 (glycoprotein 130) receptors and promote phosphorylation of STAT3 at tyrosine-705 (pY-STAT3) via Janus kinases (JAKs), STAT3 dimerization, and nuclear translocation [4]

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