Expression and Function of Four-and-a-Half LIM-domain protein 2 (FHL2) in Hepatic Fibrosis

J Sommer; C Dorn; R Weiskirchen; C Hellerbrand

doi:10.1055/s-0039-3402114

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2020; 58(01): e6
DOI: 10.1055/s-0039-3402114

Poster Visit Session I Basic Hepatology (Fibrogenesis, NPC, Transport): Friday, February 14, 2020, 12:30 pm – 1:15 pm, Lecture Hall P1

Georg Thieme Verlag KG Stuttgart · New York

Expression and Function of Four-and-a-Half LIM-domain protein 2 (FHL2) in Hepatic Fibrosis

J Sommer

¹Friedrich-Alexander-University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen, Germany

,

C Dorn

²University of Regensburg, Department of Clinical Pharmacy, Regensburg, Germany

,

R Weiskirchen

³RWTH University Hospital Aachen, Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, Aachen, Germany

,

C Hellerbrand

¹Friedrich-Alexander-University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen, Germany

⁴Friedrich-Alexander-University Erlangen-Nürnberg, Comprehensive Cancer Center, CCC Erlangen-EMN, Erlangen, Germany

› Author Affiliations

Abstract

Full Text

The four-and-a-half LIM-domain protein 2 (FHL2) is a scaffolding protein modulating multiple signal transduction pathways in a tissue- and cell context- specific manner. Some studies revealed a role of FHL2 in fibrotic diseases of different organs as well as in different types of cancer including hepatocellular carcinoma.

The aim of this study was to investigate the expression and function of FHL2 in hepatic fibrosis.

Methods and Results:

RT-qPCR and Western Blot analysis revealed that FHL2 mRNA and protein expression were significantly increased in different murine models of liver fibrosis. Furthermore, we found significantly elevated FHL2 expression in liver tissues of patients with chronic hepatitis C infection (HCV) and advanced fibrosis (staging 3 and 4) compared with HCV-patients with lower fibrosis stages. Furthermore, expression levels of FHL2 correlated significantly with the expression of collagen type I and alpha-smooth muscle actin (alpha-sma) in diseased human liver tissues. Alpha-sma is a marker for the activation of hepatic stellate cells (HSC), the key event of hepatic fibrosis. In line with this, immunohistochemistry showed a strong alpha-sma immunosignal in fibrotic septa of cirrhotic liver tissues. Furthermore, FHL2 increased significantly during the in vitro activation of primary HSCs. To further assess the role of FHL2 in liver fibrosis, we applied the bile duct ligation (BDL) model to FHL2-deficient (FHL2-ko) and wildtype (wt) mice. BDL caused a more severe portal and parenchymal inflammation as well as extended portal fibrosis in FHL2-ko compared to wt mice. In line with this, BDL-induced pro-inflammatory (TNF, IL-1, MCP-1, ICAM-1) and pro-fibrogenic (alpha-sma, TGF-beta, Collagen Type I) gene expression was significantly higher in livers of FHL2-ko compared to wt mice.

Summary and Conclusion:

The marked upregulation of FHL2 in hepatic fibrosis exhibits anti-inflammatory and anti-fibrogenic effects. These data indicate FHL2 as potential prognostic marker and therapeutic target for hepatic fibrosis in patients with chronic liver diseases.