Antagonistic regulation of transmembrane 4 L6 family member 5 attenuates fibrotic phenotypes in CCl4-treated mice

The development of liver fibrosis from chronic inflammation can involve epithelialmesenchymal transition (EMT). Severe liver fibrosis can progress to cirrhosis, and further to hepatocellular carcinoma. Because the tetraspanin transmembrane 4 L6 family member 5 (TM4SF5) induces EMT and is highly expressed in hepatocellular carcinoma, it is of interest to investigate whether TM4SF5 expression is correlated with EMT processes during the development of fibrotic liver features. Using hepatic cells in vitro and a CCl4-mediated mouse liver in vivo model, we examined whether TM4SF5 is expressed during liver fibrosis mediated by CCl4 administration and whether treatment with anti-TM4SF5 reagent blocks the fibrotic liver features. Here, we found that TM4SF5 expression was induced by the transforming growth factor (TGF)beta 1 and epidermal growth factor signaling pathways in hepatocytes in vitro. In the CCl4-mediated mouse liver model, TM4SF5 was expressed during the liver fibrosis mediated by CCl4 administration and correlated with a-smooth muscle actin expression, collagen I deposition, and TGF beta 1 and epidermal growth factor receptor signaling activation in fibrotic septa regions. Interestingly, treatment with anti-TM4SF5 reagent blocked the TM4SF5-mediated liver fibrotic features: the formation of fibrotic septa with a-smooth muscle actin expression and collagen I deposition was attenuated by treatment with anti-TM4SF5 reagent. These results suggest that TM4SF5 expression mediated by TGF beta 1 and growth factor can facilitate fibrotic processes during chronic liver injuries. TM4SF5 is thus a candidate target for prevention of liver fibrosis following chronic liver injury.