Thesis:Protective Role Of Estrogen-induced Mirna-29Expression In Carbon Tetrachloride-induced Mouse Liver Injury

Hepatic fibrosis is the pathological process of a variety of chronic liver disease to cirrhosis of liver, fibrosis is characterized by the excessive deposition of components of the extracellular matrix, predominantly collagens. Hepatic fibrosis is a common outcome of chronic hepatic injuries or diseases and can ultimately lead to liver cirrhosis and hepatic failure. Previous studies have indicated that female animals are more resistant to carbon tetrachloride (CC14)-induced liver fibrosis than male animals, and that estradiol (E2) treatment can inhibit CC14-induced animal hepatic fibrosis. The underlying mechanism governing these phenomena, however, has not been fully elucidated.MicroRNAs (miRNAs) are a class of noncoding RNAs that regulate target gene expression at the posttranscriptional level. It has been widely reported that aberrant miRNA expression can lead to the development of multiple diseases. A number of reports have demonstrated that an important role is played by miRNAs during the activation of HSCs. Here we reported the role of estrogen-induced miRNA-29(miR-29) expression in CCl4-induced mouse liver injury. In our study, we firstly found the levels of miR-29aand miR-29b expression were significantly decreased in the livers of male, but not female, mice following four weeks of CCl4treatment. The downregulation 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, E2was maintained at a higher level in female mice than in male mice. In contrast to TGF-β1that decreased miR-29a/b expression in murine hepatoma IAR20cells and normal hepatocytes, E2enhanced the expression of miR-29a/b through suppressing nuclear factor-κB (NF-κB) signal pathway, which negatively regulates miR-29expression. Furthermore, both E2treatment and intravenously injection of the recombinant adenovirus expressing miR-29a/b markedly increased miR-29a/b level and attenuated the expression of fibrotic markers in mouse livers during CCl4treatment, supporting the protective role of E2-induced miR-29in 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...