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上海士鋒關(guān)于VDR配體可抑制肝纖維化的介紹
點(diǎn)擊次數(shù)：927 發(fā)布時(shí)間：2013-5-8
VDR配體對(duì)肝纖維化的調(diào)控
肝纖維化（Liver fibrosis）是可逆的愈傷反應(yīng)，肝星狀細(xì)胞（hepatic slate cells, HSCs）的TGFβ1/SMAD活化參與了這個(gè)過(guò)程。它由細(xì)胞外基質(zhì)成分的過(guò)度沉積而引起，可導(dǎo)致肝功能損害。
這項(xiàng)研究發(fā)現(xiàn)，維生素D受體（vitamin D receptor, VDR）的配體可通過(guò)TGFβ1來(lái)抑制HSC活性和消除肝纖維化，而Vdr基因敲除小鼠會(huì)自發(fā)形成肝纖維化。研究人員發(fā)現(xiàn)，TGFβ1信號(hào)可導(dǎo)致在HSC中基因組范圍內(nèi)VDR結(jié)合位點(diǎn)（VDR順?lè)唇M,VDR cistrome）的重新分布，并促進(jìn)在SMAD3纖維化靶基因與VDR的結(jié)合，這是通過(guò)TGFβ1依賴性染色質(zhì)重組而實(shí)現(xiàn)的。在VDR配基存在的情況下，VDR與共調(diào)控基因的結(jié)合，可以減少SMAD3對(duì)這些位點(diǎn)的占據(jù)，從而抑制纖維化。
這些實(shí)驗(yàn)結(jié)果揭示了一個(gè)相互關(guān)聯(lián)的可調(diào)節(jié)肝纖維化的VDR/SMAD基因組通路，并確認(rèn)了VDR可作為內(nèi)分泌檢查點(diǎn)（checkpoint）來(lái)對(duì)肝臟愈傷反應(yīng)進(jìn)行調(diào)控。更重要的是，這項(xiàng)研究成果預(yù)示了VDR配體可以作為肝纖維化的一種潛在治療手段。
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