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A Master Cistromic Circuit Governing Hepatic Fibrogenesis


Liver fibrosis is a reversible wound-healing response involving TGFβ1 activation of hepatic stellate cells (HSCs). However, the molecular mechanisms governing fibrogenesis remain unclear. Here we show that vitamin D receptor (VDR) ligands inhibit HSC activation and abrogate liver fibrosis, while VDR knockout mice spontaneously developed hepatic fibrosis. Mechanistically, we identify a cryptic VDR cistrome in HSCs that is elicited by a TGFβ1 pro-fibrotic insult. This cistrome overlaps extensively with the SMAD3 cistrome and includes a large number of pro-fibrotic genes. Notably, SMAD3 occupancy at co-regulated genes was significantly reduced by VDR ligand treatment, identifying a VDR/SMAD cistromic circuit as a master regulator of hepatic fibrogenesis. These results define key roles for Vitamin D in maintaining hepatic homeostasis as well as in modulating the intensity of the injury response, suggesting SMAD cistromic restriction by VDR ligands as a treatable mechanism to ameliorate liver fibrosis. HIGHLIGHTS Hepatic stellate cell (HSC) activation is reversed by Vitamin D receptor (VDR) ligands VDR knockout mice spontaneously develop liver fibrosis TGFβ unlocks a cryptic VDR cistrome in HSCs VDR antagonizes SMAD3/TGFβ-activated pro-fibrotic genes

Type Journal
Authors Ning Ding1, Ruth T. Yu1, Nanthakumar Subramaniam3, Mathias Leblanc1, Caroline Wilson3, Renuka Rao3, Mingxiao He1, Sally Coulter3, Christopher Scott3, Mara Sherman1, Sue L. Lau4, Annette R. Atkins1, Grant D. Barish1, Jenny E. Gunton4, Christopher Liddle3, Michael Downes1, Ronald M. Evans1,2
Garvan Authors Prof Jenny Gunton
Publisher Name CELL
Published Date 2013-04-26 00:00:00
Status Published