Atrophin 2 expression in chronic liver disease functionally affects activated hepatic stellate cells

Atrophin proteins have first been identified in dentatorubral-pallidoluysian atrophy. Atrophin family proteins have been identified as nuclear receptor corepressors. Atrophins are involved in the regulation of various biological processes including migration and orientation, and altered atrophin expression has been shown in neurodegenerative disease and cancer. Atrophin2 (ATN2) has critical functions in normal mouse embryonic development whereas Atrophin1 is dispensable. The role of atrophins in healthy and diseased liver is unknown.

The aim of this study was to analyze the expression and function of ATN2 in chronic liver disease.

Methods and Results: Hepatic ATN2 expression was significantly increased in mice exposed to chronic liver injury with CCl4 or fed with a NASH-inducing diet. In contrast hepatic ATN2 levels in a model of hepatic steatosis without significant inflammation and fibrosis did not differ significantly compared with normal liver tissue. However, ATN2 was significantly increased in primary murine and human hepatic stellate cells (HSC) during the course of in vitro activation. By transient transfection with siRNA we achieved a more than 50% reduction of ATN2 in activated HSCs. Based on the known association of ATN2 with cancer we further assessed ATN2 expression in 4 different human HCC cell-lines and found a marked up-regulation compared to primary human hepatocytes.

Conclusions: Our data indicate ATN2 as functionally relevant transcriptional regulator in activated HSCs, and eventually also in hepatocancerogenesis. Herewith, ATN2 appears as potential target to inhibit the progression of chronic liver disease.