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

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

来源：Cell, 2013, 153(3): 601-613.

DOI：10.1016/j.cell.2013.03.028

Liver fibrosis is a reversible wound-healing response involving TGF beta 1/SMAD activation of hepatic stellate 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 TGF beta 1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGF beta 1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGF beta 1-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.

• 出版日期2013-4-25
• 单位河北医科大学