Protective Role of Estrogen-induced miRNA-29 Expression in Carbon Tetrachloride-induced Mouse Liver Injury

Previous studies have indicated that female animals are more resistant to carbon tetrachloride (CCl4)-induced liver fibrosis than male animals, and that estradiol (E-2) treatment can inhibit CCl4-induced animal hepatic fibrosis. The underlying mechanism governing these phenomena, however, has not been fully elucidated. Here we reported the role of estrogen-induced miRNA-29 (miR-29) expression in CCl4-induced mouse liver injury. Hepatic miR-29 levels were differentially regulated in female and male mice during CCl4 treatment. Specifically, the levels of miR-29a and miR-29b expression were significantly decreased in the livers of male, but not female, mice following 4 weeks of CCl4 treatment. The down-regulation of miR-29a and miR-29b in male mouse livers correlated with the early development of liver fibrosis, as indicated by increased expressions of fibrotic markers in male mice relative to female mice. In addition, E-2 was maintained at a higher level in female mice than in male mice. In contrast to TGF-beta 1 that decreased miR-29a/b expression in murine hepatoma IAR20 cells and normal hepatocytes, E-2 enhanced the expression of miR-29a/b through suppression of the nuclear factor-kappa B (NF-kappa B) signal pathway, which negatively regulates miR-29 expression. Furthermore, both E-2 treatment and intravenous injection of the recombinant adenovirus expressing miR-29a/b markedly increased the miR-29a/b level and attenuated the expression of fibrotic markers in mouse livers during CCl4 treatment, supporting the protective role of E-2-induced miR-29 in CCl4-induced hepatic injury. In conclusion, our results collectively demonstrate that estrogen can inhibit CCl4-induced hepatic injury through the induction of hepatic miR-29.