Disruption of Estrogen Receptor Alpha in rats results in faster initiation of compensatory regeneration despite higher liver injury after carbon tetrachloride treatment

摘要

Estrogen receptor alpha (ESR1) is one of the two intracellular receptors for estrogen and is expressed by hepatocytes in the liver. The role of ESR1 in the regulation of toxicant-induced liver injury and compensatory regeneration is not completely clear. We investigated the role of ESR1 in liver regeneration after carbon tetrachloride (CCl4)-induced liver injury using wild type (WT) and ESR1 knockout rats (ESR1-KO). Adult female WT and ESR1-KO rats were treated with 1ml/kg CCl4 and euthanized over a time course of 0–48 hr. Liver Injury measured by serum alanine amino transaminase (ALT) and histopathological analysis showed significantly higher liver injury in ESR1-KO as compared to WT rats. Hematoxylin and eosin (H&E) staining revealed two-fold higher necrosis and significant inflammatory cell infiltration in ESR1-KO rats. Chloracetate esterase staining revealed higher neutrophil infiltration in ESR1-KO rat livers. Interestingly, Proliferating cell nuclear antigen (PCNA) immunohistochemistry showed that in spite of two-fold higher liver injury, the ESR1KO rats had equal liver regeneration as compared to WT rats. Western blot analysis of cyclin D1 and phosphorylated Rb, proteins involved in the initiation of the cell cycle, were significantly higher at all time points in ESR1KO rats. Further analysis revealed faster activation of canonical Wnt/β-catenin and NF-κB signaling in ESR1-KO rats characterized by higher activated β-catenin and phosphorylated p65 at 12 hr after CCl4 treatment. Taken together, these data indicate that ESR1-mediated signaling inhibits liver regeneration by down regulation of Wnt signaling resulting in lower cyclin D1 activation after chemical-induced liver injury.