Sex hormone-binding globulin restrains hepatic fibrosis via inhibition of Tgfβ expression

Despite the advances in the development of therapeutic strategies for liver cirrhosis, finding novel molecular targets for drug discovery is still needed to broaden clinically available options. Sex hormone-binding globulin (SHBG) is an abundant circulating protein in the human bloodstream, which is reported to reduce pro-inflammatory cytokines and dampen liver cancer. However, its role in liver fibrosis has never been reported. In the human specimen and gene expression omnibus dataset, SHBG protein was accumulated around the fibrosis area, and SHBG expression was strongly inverse related to human liver fibrosis. By using SHBG-transgenic mice, we tried to elucidate the possible protective role of SHBG in liver fibrosis. Under chronic liver inflammatory conditions (DEN + NMOR, 32 weeks of age), SHBG-transgenic mice were resistant to liver fibrosis development. With scarce fibrotic areas in Masson-Goldner's trichrome staining and alpha-smooth muscle actin immunostaining, SHBG-transgenic mice significantly decreased transforming growth factor β (Tgfβ) expression and downstream signals. Under AXL inhibition, SHBG did not suppress Tgfβ suppression and downstream signals. SHBG transgenic mice reduced mesenchymal marker expression in fibrotic liver. When Lx-2 cells activated by damage-associated molecular patterns were treated with SHBG, the conditioned media suppressed mesenchymal marker expression and reduced the migration rate of SNU423 cells compared to the vehicle-treated group. Collectively, we suggest SHBG as a host protective factor and novel molecular target for liver fibrosis. KEY MESSAGES: The abundant human plasma protein, sex hormone binding globulin (SHBG), accumulates in fibrotic liver and associates with extended survival of cirrhotic patients. SHBG represses liver fibrosis development in chronic inflammatory mouse model. SHBG suppresses Tgfβ transcription level through AXL reduction.