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Deletion of Estrogen Receptor Alpha in Rats Speeds up Liver regeneration After CCl4‐ induced Liver Injury
Author(s) -
McGreal Steven,
Rumi M.A Karim,
Soares Michael,
Apte Udayan
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.56.12
Subject(s) - estrogen receptor alpha , estrogen receptor , endocrinology , medicine , proliferating cell nuclear antigen , wnt signaling pathway , cyclin d1 , liver injury , liver regeneration , western blot , estrogen , chemistry , immunohistochemistry , regeneration (biology) , biology , signal transduction , microbiology and biotechnology , cancer , cell cycle , breast cancer , biochemistry , gene
Estrogen receptor alpha (Esr1) is one of the two cognate receptors for Estrogen and is expressed by hepatocytes. The role of ESR1 in liver regeneration is not completely clear. We studied the role of ESR1 in liver regeneration after CCl 4 ‐induced liver injury using type (WT) and ESR1 knockout (ESR1‐KO) rats. Two‐three month old female WT and ESR1‐KO rats were treated with 1ml/kg CCl 4 and euthanized over a time course of 0–48 hr. Liver Injury measured by serum ALT and histopathology increased substantially after CCl 4 treatment but no significant difference in liver injury between WT and ESR1‐KO was noted. H&E staining shows an early increase in hepatic inflammation starting at 12 hr post CCl 4 along with moderately higher mRNA for various inflammatory markers. Histopathological analysis indicated a rapid recovery in ESR1‐KO mice resulting in significantly lower necrosis at 48 hr after CCl 4 treatment. Immunohistochemistry shows an early appearance of PCNA positive cells in KO livers as compared to WT livers, which sustained through 24 hr. Western blot analysis showed an elevated level of Cyclin D1 and phosphorylated Rb protein in the KO rats at 12 and 24 hr. Further analysis revealed faster activation of canonical Wnt/β‐catenin signaling in ESR1‐KO rats characterized by higher activated β‐catenin accompanied with increased phosphorylated GSK3β at 12 hr after CCl 4 treatment. Taken together, these data indicate that signaling via ESR1 inhibits liver regeneration by down regulation of Wnt signaling resulting in lower Cyclin D1 activation after chemical induced liver injury. Support or Funding Information T32 training grant (5T32ES007079‐34), R01DK098414, and Pilot Grant from Institute for Reproductive Health and Regenerative Medicine (IRHRM) of KUMC