H19 promotes cholestatic liver fibrosis by preventing ZEB1‐mediated inhibition of epithelial cell adhesion molecule

Abstract

Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic lncRNA 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 ALT, AST, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL vs Null-BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19-BDL mice showed significant enrichment of CD3+γδ+, IL-4, and IL-17 producing CD4+ and CD8+ immune cell populations. H19 downregulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1) but upregulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)-box 9 (SOX9) 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 (MSC) and to a lesser extent in mouse large cholangiocytes (MLC). The upregulation of H19RNA and EpCAM correlated positively with the downregulation of ZEB1 in primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) liver specimens. Conclusions: The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway.

Long non-coding RNA in liver metabolism and disease: Current status

“…41 Hepatic overexpression of H19RNA facilitated the development of obstructive cholestatic liver fibrosis. 42 Mechanistically, H19 downregulated hepatic zinc finger E-box-binding homeobox 1 (ZEB1), and impeded its suppression of epithelial cell adhesion molecule (EpCAM), which in turn augmented bile duct ligation (BDL)-induced liver fibrosis. In addition, H19RNA is upregulated in both PBC and PSC patients.…”

LncRNA AK054921 and AK128652 are potential serum biomarkers and predictors of patient survival with alcoholic cirrhosis

“…They also play a role in epigenetic regulation of the DNA 24 . Over the past few years, there are significant advancements to explore the critical roles of lncRNAs in the disease processes 13, 14, 17, 25–28 . Further, measuring the levels of lncRNA expression has been investigated as the disease biomarkers, either for diagnostic or prognostic purposes.…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…Overexpression of BCL2 in mice was reported to disrupt BA metabolism and resulted in cholestatic liver fibrosis and up‐regulated lncRNA H19 expression 56. LncRNA H19 is a tumor suppressor and is involved in the dysregulation of lipid homeostasis, diabetes, and cancer 57, 58, 59. In addition, SHP was identified as a novel transcriptional repressor of H19 expression.…”