Here we evaluate the effects of activation of the bile acid receptor pathways MAPK Inhibitor high throughput screening in liver sinusoidal endothelial cells using microarray analysis. Methods: A murine LSEC line was treated with a dual FXR/TGR5 agonist (INT767, 30uM) and/or free fatty acids (palmitic acid and oleic acid, 0.66mM) for 24 hours. RNA was isolated and gene expression analysis was performed using the GeneChip Mouse Gene 2.0 ST Array. Analysis of deferentially

expressed genes, canonical signaling pathways and upstream regulators was analyzed using the Ingenuity Pathway Analysis (IPA) software. Differential regulation was defined as 1.5-fold difference from untreated LSEC (p<0.05, ANOVA). Results: Gene expression analysis revealed that 29 genes were uniquely downregulated following treatment with INT-767. A number of these downregulated genes have been shown to be important in fibrosis and inflammation. IL-33,

a member of the IL-1 super-family, was significantly decreased following treatment with the agonist (p=0.009). In addition, the expression targets for pro-fibrotic (TGFbeta; p=0.001) and pro-inflammatory (IL-12, p=0.04) master regulators were over-represented in our genes responding to treatment. These pathways were predicted Cabozantinib in vitro by IPA to be inhibited by treatment with INT-767. Conclusion: We demonstrate that activation of the bile acid receptor pathways in murine LSECs results in a down regulation of pro-fibrotic and pro-inflammatory genes. Understanding the effects of FXR and TGR5 activation in LSEC could be important for both NAFLD and other liver diseases. Disclosures: Luciano Adorini – Consulting: Intercept Pharmaceuticals Moshe Levi – Grant/Research Support: Intercept, Genzyme-Sanofi The following people medchemexpress have nothing to disclose: Rachel McMahan, Cara Porsche, Michael Edwards, Hugo R. Rosen Objectives:

Thyroid hormone (TH) is important for liver repair because it regulates hepatic differentiation. Both serum TH levels and hepatic deiodinases control intrahepatic TH activity. TH substrate (thyroxine, T4) is converted into active hormone (triidothyronine, T3) by deiodinase 1 (D1), but into inactive hormone (reverse T3, rT3) by deiodinase 3 (D3). D3 transcription is controlled by Hedgehog-regulated factors. Hedgehog signaling increases during liver injury. Liver injury also changes the relative expressions of D1 and D3. However, the cell types and signaling mechanisms involved are unclear. We evaluated the hypothesis that changes in hepatic deiodinases result from repair-related activation of the Hedgehog pathway in stromal cells. Methods: We localized deiodinase expression to specific liver cell types and assessed deiodinase changes during injury by performing bile duct ligation (BDL) in rats.