Vitamin D alleviates liver fibrosis by inhibiting histidine-rich calcium binding protein (HRC)

Liver fibrosis may progress toward cirrhosis and cancer without effective therapy. Here, we investigated the underlying mechanism of Vitamin D as a therapeutic approach. 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 proliferation of cells transfected with HRC +/+ and HRC−/- plasmids was detected by MTS and cell cycle methods. 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. Vitamin D can delay hepatic fibrosis by reducing 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.