Vitamin D Alleviates Liver Fibrosis By Downregulating HRC In Mice

Objective:Liver fibrosis is a wound healing response to chronic liver injury and characterized by excessive deposition of extracellular matrix（ECM）proteins including fibrillar collagens.Liver fibrosis may progress toward cirrhosis and cancer without effective therapy.Here,we investigated the underlying mechanism of Vitamin D as a therapeutic approach.Methods:Carbon tetrachloride（CCL₄）-induced mice model and transforming growth factor-β1（TGF-β1）induced human hepatic stellate cell line LX-2 were used in vivo and in vitro.The fibrotic profiles,degree of liver injury and HRC expression were assessed by histology,Western blot,immunohistochemistry and Real-Time PCR.The related genes expression and proliferation of cells transfected with HRC+/+and HRC-/-plasmids was detected by Western Blot,RT-PCR,MTS and cell cycle methods.Results:Vitamin D significantly suppressed the expression of HRC in liver fibrosis model both in vivo and in vitro（P<0.01）.The cell with overexpression of HRC significantly increased TGF-β1/Smad3 expressions and the percentage of the S peak in cell cycle（P<0.05）.However,Vitamin D can significantly reverse the levels of TGF-β1,Smad3 and p-smad3 caused by HRC in vitro.Furthermore,the overexpression of HRC in cell lines can attenuate the function of Vitamin D,suggesting that VD played a role by regulating HRC.Mechanically,HRC as the target of VDR is detected by CHIP method.Conclusion:Vitamin D can delay liver fibrosis by inhibiting activation of hepatic stellate cells and TGF-β/Smad signaling through negative regulation of HRC.The findings revealed the important regulatory effect of Vitamin D in hepatic stellate cells and provided new insights into the therapeutic function of Vitamin D on liver fibrosis.