title: A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response.
abstract: Liver fibrosis is a reversible wound-healing response involving TGFβ1/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 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.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.forename: Nanthakumar
authors.initials: N
authors.lastname: Subramaniam
authors.forename: Mara H
authors.initials: MH
authors.lastname: Sherman
authors.forename: Caroline
authors.initials: C
authors.lastname: Wilson
authors.forename: Renuka
authors.initials: R
authors.lastname: Rao
authors.forename: Mathias
authors.initials: M
authors.lastname: Leblanc
authors.forename: Sally
authors.initials: S
authors.lastname: Coulter
authors.forename: Mingxiao
authors.initials: M
authors.lastname: He
authors.forename: Christopher
authors.initials: C
authors.lastname: Scott
authors.forename: Sue L
authors.initials: SL
authors.lastname: Lau
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.forename: Grant D
authors.initials: GD
authors.lastname: Barish
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gunton
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives; D005355:Fibrosis / Q000517:prevention & control; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D055166:Hepatic Stellate Cells; D008099:Liver / Q000293:injuries / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D059467:Transcriptome; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1; C055085:calcipotriene; D002117:Calcitriol