SUMMARY Liver fibrosis is a reversible wound-healing response involving TGFβ1 activation of hepatic stellate cells (HSCs). 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 describe a pronounced redistribution of genome wide VDR binding sites (VDR cistrome) in HSCs elicited by a TGFβ1 pro-fibrotic insult. This TGFβ1-induced VDR cistrome overlaps extensively with SMAD3 binding sites, with co-occupancy at numerous cis-regulatory elements identified on a large set of pro-fibrotic genes. Addition of VDR ligand reduces SMAD3 occupancy at co-regulated genes, revealing an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis. These results define a role for VDR as a endocrine checkpoint to modulate the wound healing response in liver, and suggest VDR ligands as a potential therapy for liver fibrosis.

Highlights d Genetic and dietary risk factors for colorectal cancer converge on the BA-FXR axis d FXR controls proliferating Lgr5 + intestinal stem cells d FXR agonists curtail colorectal cancer progression

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Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.

Summary Management of energy stores is critical during endurance exercise, with a shift in substrate utilization from glucose towards fat being a hallmark of trained muscle. Here we show that this key metabolic adaptation is both dependent on muscle PPARδ and stimulated by PPARδ ligand. Furthermore, we find that muscle PPARδ expression positively correlates with endurance performance in BXD mouse reference populations. In addition to stimulating fatty acid metabolism in sedentary mice, PPARδ activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels PPARδ acts to delay the onset of hypoglycemia and extends running time by ~100 minutes in treated mice. Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies and unavoidably, the enhancement of athletic performance.