Publications

Abstract

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