上海士锋生物关于VDR配体对肝纤维化的调控的报告

VDR配体对肝纤维化的调控

肝纤维化（Liver fibrosis）是可逆的愈伤反应，肝星状细胞（hepatic slate cells, HSCs）的TGFβ1/SMAD活化参与了这个过程。它由细胞外基质成分的过度沉积而引起，可导致肝功能损害。

这项研究发现，维生素D受体（vitamin D receptor, VDR）的配体可通过TGFβ1来抑制HSC活性和消除肝纤维化，而Vdr基因敲除小鼠会自发形成肝纤维化。研究人员发现，TGFβ1信号可导致在HSC中基因组范围内VDR结合位点（VDR顺反组,VDR cistrome）的重新分布，并促进在SMAD3纤维化靶基因与VDR的结合，这是通过TGFβ1依赖性染色质重组而实现的。在VDR配基存在的情况下，VDR与共调控基因的结合，可以减少SMAD3对这些位点的占据，从而抑制纤维化。

这些实验结果揭示了一个相互关联的可调节肝纤维化的VDR/SMAD基因组通路，并确认了VDR可作为内分泌检查点（checkpoint）来对肝脏愈伤反应进行调控。更重要的是，这项研究成果预示了VDR配体可以作为肝纤维化的一种潜在治疗手段。

A Vitamin D Receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response

Ning Ding, Ruth T. Yu, Nanthakumar Subramaniam, Mara H. Sherman, Caroline Wilson, Renuka Rao, Mathias Leblanc, Sally Coulter, Mingxiao He, Christopher Scott, Sue L. Lau, Annette R. Atkins, Grant D. Barish, Jenny E. Gunton, Christopher Liddle, Michael Downes, Ronald M. Evans

Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic slate cells （HSCs）. It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor （VDR） ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites （VDR cistrome） in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis.