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

Yaqin Zhang,Linping Wu,Yang Wang,Mingcao Zhang,Limin Li,Dihan Zhu,Xihan Li,Hongwei Gu,Chen-Yu Zhang,Ke Zen

doi:10.1074/jbc.m111.314922

Abstract

Previous studies have indicated that female animals are more resistant to carbon tetrachloride (CCl(4))-induced liver fibrosis than male animals, and that estradiol (E(2)) treatment can inhibit CCl(4)-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 CCl(4)-induced mouse liver injury. Hepatic miR-29 levels were differentially regulated in female and male mice during CCl(4) 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 CCl(4) 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-β1 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-κB (NF-κB) 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 CCl(4) treatment, supporting the protective role of E(2)-induced miR-29 in CCl(4)-induced hepatic injury. In conclusion, our results collectively demonstrate that estrogen can inhibit CCl(4)-induced hepatic injury through the induction of hepatic miR-29.

Highlights

Mechanism underlying the protection of estradiol against CCl4-induced hepatic fibrosis remains unclear
In agreement with the results of tissue staining, which demonstrated that liver fibrosis occurred in male mice but not female mice, we observed that, TGF-␤1 was up-regulated in the livers of both male and female mice, ␣-SMA and collagen I levels were only significantly increased in the livers of male mice, but not female mice
Liver fibrosis is a complex process modulated by a set of signaling pathways and results in the deposition of extracellular matrix proteins during fibrogenesis [35,36,37]

Summary

Introduction

Mechanism underlying the protection of estradiol against CCl4-induced hepatic fibrosis remains unclear. Results: miR-29 expression was differentially regulated in male/female mice during CCl4 treatment. Both estradiol and miR29a/b-expressing adenovirus increased hepatic miR-29a/b levels and attenuated CCl4-induced hepatic fibrosis. We reported the role of estrogen-induced miRNA-29 (miR-29) expression in CCl4-induced mouse liver injury. In contrast to TGF-␤1 that decreased miR-29a/b expression in murine hepatoma IAR20 cells and normal hepatocytes, E2 enhanced the expression of miR-29a/b through suppression of the nuclear factor-␬B (NF-␬B) signal pathway, which negatively regulates miR-29 expression Both E2 treatment and intravenous injection of the recombinant adenovirus expressing miR-29a/b markedly increased the miR29a/b level and attenuated the expression of fibrotic markers in mouse livers during CCl4 treatment, supporting the protective role of E2-induced miR-29 in CCl4-induced hepatic injury. Our results collectively demonstrate that estrogen can inhibit CCl4-induced hepatic injury through the induction of hepatic miR-29

Objectives

Results

Conclusion