Yongfeng Song1,2, Chune Liu1, Xia Liu3, Jocelyn Trottier4, Michele Beaudoin1, Li Zhang1, Chad Pope5, Guangyong Peng3, Olivier Barbier4, Xiaobo Zhong5, Linheng Li6, Li Wang1,7,8,9. 1. Department of Physiology and Neurobiology, and Institute for Systems Genomics, University of Connecticut, Storrs, CT. 2. Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, China. 3. Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St. Louis, MO. 4. Laboratory of Molecular Pharmacology, CHU-Québec Research Centre and Faculty of Pharmacy, Laval University, Québec, Canada. 5. Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT. 6. Stowers Institute for Medical Research, Kansas City, MO. 7. Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT. 8. Veterans Affairs Connecticut Healthcare System, West Haven, CT. 9. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract
Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic long noncoding RNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)-induced liver fibrosis, which was accompanied by the elevation of serum alanine aminotransferase, aspartate aminotransferase, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL versus null-BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19-BDL mice showed significant enrichment of CD3+γδ+, interleukin-4, and interleukin-17 producing CD4+ and CD8+ immune cell populations. H19 down-regulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1) but up-regulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)-box 9 expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription. H19RNA impeded ZEB1's inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19-induced fibrosis; the latter was also prevented in H19-/- mice. H19RNA was markedly induced by bile acids in mouse small cholangiocytes and to a lesser extent in mouse large cholangiocytes. The up-regulation of H19RNA and EpCAM correlated positively with the down-regulation of ZEB1 in primary sclerosing cholangitis and primary biliary cirrhosis liver specimens. CONCLUSION: The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway. (Hepatology 2017;66:1183-1196).
Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic long noncoding RNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)-induced liver fibrosis, which was accompanied by the elevation of serum alanine aminotransferase, aspartate aminotransferase, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL versus null-BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19-BDL mice showed significant enrichment of CD3+γδ+, interleukin-4, and interleukin-17 producing CD4+ and CD8+ immune cell populations. H19 down-regulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1) but up-regulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)-box 9 expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription. H19RNA impeded ZEB1's inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19-induced fibrosis; the latter was also prevented in H19-/- mice. H19RNA was markedly induced by bile acids in mouse small cholangiocytes and to a lesser extent in mouse large cholangiocytes. The up-regulation of H19RNA and EpCAM correlated positively with the down-regulation of ZEB1 in primary sclerosing cholangitis and primary biliary cirrhosis liver specimens. CONCLUSION: The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway. (Hepatology 2017;66:1183-1196).
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