Increased expression of histone deacetylase 7 during hepatic stellate cell activation promotes pro-fibrogenic gene expression

K Freese; C Dorn; WE Thasler; M Müller; C Hellerbrand

doi:10.1055/s-0035-1567956

Zeitschrift für Gastroenterologie, Table of Contents

Increased expression of histone deacetylase 7 during hepatic stellate cell activation promotes pro-fibrogenic gene expression

K Freese ¹, C Dorn ¹, WE Thasler ², M Müller ¹, C Hellerbrand ¹

¹University Hospital Regensburg, Department of Internal Medicine I, Regensburg, Germany
²Hospital of the University of Munich, Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Munich, Germany

Abstract

Recent evidence has highlighted a pathological imbalance in hepatic fibrosis between the acetylation and deacetylation of histone proteins regulated by histone deacetylases (HDACs). However, the role of individual HDACs in liver fibrosis is almost completely unknown. Recently, we identified that HDAC7 can bind to the promotor of the hepatocyte growth factor (HGF) gene, and herewith, suppresses the expression of this anti-fibrogenic factor in activated hepatic stellate cells (Hepatology. 2014 Sep;60(3):1066 – 81).

The aim of this study was to get further insight into the expression and function of HDAC7 in chronic liver disease.

Methods and Results: HDAC7 expression was significantly increased in different murine models of chronic liver injury (bile duct ligation, thioacetamide intoxication and diet induced non-alcoholic steatohepatitis (NASH)) as well as in liver specimens from patients with NASH or liver cirrhosis of different origin compared to healthy control liver tissue. HDAC7 expression revealed a significant correlation with the expression of collagen type I as well as alpha-smooth muscle actin, a marker of hepatic stellate cell (HSC) expression. In line with this, HDAC7 mRNA and protein expression markedly increased during in vitro activation of murine as well as human HSCs. Stimulation with platelet-derived growth factor beta (PDGFB) further dose dependently induced HDAC7 expression in activated HSCs. Suppression of HDAC7 expression with si-RNA caused significantly reduced MMP10 expression in activated HSCs. In line with this, analysis of HDCA7 and MMP10 expression in activated HSCs from 14 different human donors showed a significant correlation. Moreover, HDCA7 expression correlated with collagen type I expression in these 14 HSCs.

Conclusion: Increased HDAC7 expression during HSC activation causes induction of profibrogenic genes and may also at least in part explain PDGFB induced profibrogenic effects on activated HSCs. Together with our previous finding that HDAC7 suppresses anti-fibrogenic HGF expression these data indicate HDAC7 as critical orchestrator of the pathologically impaired histone (de)acetylation in liver fibrosis.

Corresponding author: Hellerbrand, Claus

E-Mail: claus.hellerbrand@ukr.de