Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic Stellate Cells and Liver Fibrogenesis in Mice

Abstract Background & Aims The role of aryl hydrocarbon receptor (AHR) in liver fibrosis is controversial, because loss and gain of AHR activity each lead to liver fibrosis. The goal of this study is to investigate how the expression of AHR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice. Methods We studied the effects of AHR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-seq analysis. C57BL/6J mice were given the AHR agonists TCDD or ITE, or carbon tetrachloride (CCl 4 ), or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting. Results AHR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AHR-knockout mice was accelerated, compared to HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor beta (TGFB)-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis following administration of CCl 4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl 4 -induced liver fibrosis, whereas mice without HSC AHR given ITE did develop CCl 4 -induced liver fibrosis. In studies of mouse and human HSCs, we found that AHR prevents TGFB-induced fibrogenesis by disrupting the interaction of SMAD3 with beta-catenin, which prevents the expression of genes that mediate fibrogenesis. Conclusions In studies of human and mouse HSCs, we found that AHR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of non-toxic AHR agonists or strategies to activate AHR signaling in HSCs might be developed to prevent or treat liver fibrosis.