Mediator subunit MED1 deficiency prevents carbon tetrachloride induced hepatic fibrosis in mice.

Mediator subunit MED1 mediates ligand-dependent binding of the Mediator coactivator complex to various nuclear receptors and plays critical role in embryonic development, lipid and glucose metabolism, liver regeneration and tumorigenesis. However, the precise role of MED1 in the development of liver fibrosis has been unclear. Here, we showed that MED1 expression was increased in livers from nonalcoholic steatohepatitis (NASH) patients and mice, and positively correlated with TGF-β signaling and pro-fibrotic factors. Upon with CCl4 treatment,hepatic fibrosis was much lesser in liver specific MED1 deletion (MED1Δ Liv ) mice than in MED1fl/fl littermates. TGF-β/Smad2/3 signaling pathway was inhibited, and gene expression of fibrotic markers, including α-smooth muscle actin (α-SMA), collagen type 1 alpha 1 (Col1a1), matrix metalloproteinase-2 (Mmp2), and metallopeptidase inhibitor 1 (Timp1) were decreased in livers of MED1Δ Liv mice with CCl4 injection. Transcriptomic analysis revealed that the differentially expressed genes in livers of CCl4 -adminstered MED1Δ Liv mice were enriched in pathway of oxidoreductase activity, following with robustly reduced oxidoreductase activity related genes, such as Gm4756, Txnrd3, and Etfbkmt. More importantly, we found that reduction of reactive oxygen species (ROS) in MED1knockdown hepatocytes blocked the activation of TGF-β/Smad2/3 pathway and the expression of fibrotic genes in LX2 cells. These results indicate that MED1 is a positive regulator for hepatic fibrogenesis and MED1 may be considered as a potential therapeutic target for the regression of liver fibrosis.