# LncRNA H19 in Cholestatic Liver Diseases

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $536,469

## Abstract

Cholangiopathies, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), are
characterized by damage and dysfunction of bile duct epithelial cells (cholangiocytes). Recently, long noncoding
RNAs (lncRNAs) have been identified as a novel class of master regulators of gene expression and are linked
to many fundamental biological processes and various human diseases including various liver diseases.
However, little is known regarding the role of lncRNAs in the regulation of cholangiocyte function and
pathogenesis of hepatobiliary diseases. The overall goal of the current application is to identify the roles and
mechanisms of lncRNAs in biliary dysfunction under cholestatic conditions and to create a fundamental base for
developing novel therapeutic strategies for cholangiopathies. The expression of lncRNAs is tissue-, cell type-
and differentiation stage-specific. LncRNA H19 is the first identified imprinted lncRNA and is highly conserved
across lineages. It has been reported that H19 is the most strongly differentially expressed lncRNA during liver
development and has been linked to hepatic metastases from a range of human carcinomas and cholestatic liver
injury. However, the regulatory role of H19 in cholangiocyte pathophysiology remains unknown and is the focus
of the current application. Our most recent studies discovered that H19 is highly expressed in cholangiocytes,
but not in hepatocytes under physiological conditions and hepatic H19 expression levels are correlated with
upregulation of S1PR2 and cholestatic liver injury in the multi-drug resistance 2 knockout (Mdr2-/-) mouse, a well-
established mouse model of PSC and PSC patient liver. Our preliminary data further showed that 1) BDL
significantly up-regulated H19 and down-regulated the apical sodium bile acid transporter (ASBT) and
sodium/taurocholate co-transporting polypeptide (NTCP); 2) BDL-induced cholestatic liver injury was markedly
reduced in H19ΔExon1/+ mouse; 3) Knocking down H19 not only significantly reduced taurocholate (TCA)-
induced expression of fibrotic genes and S1PR2 in cholangiocytes, but also markedly upregulated hepatic small
heterodimer partner (SHP) expression and reduced cholestatic injury in Mdr2-/- mice; 4) Hepatic H19 level was
also significant upregulated in the carbon tetrachloride (CCl4)-induced cholestatic liver injury mouse model.
Based on these observations, we HYPOTHESIZE that lncRNA H19 plays an important role in the regulation
of hepatobiliary epithelial function by disruption of hepatic bile acid homeostasis. Two specific aims are
proposed to test this hypothesis. 1) To define the role of lncRNA H19 in the regulation of bile acid-mediated
cholangiocyte growth and remodeling during cholestatic liver injury; 2) To identify the mechanisms by
which bile acids upregulate lncRNA H19 in cholestatic conditions. Completion of the proposed studies will
make a significant conceptual advance by linking the lncRNA H19-mediated regulation o...

## Key facts

- **NIH application ID:** 9971523
- **Project number:** 5R01DK115377-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** PHILLIP B HYLEMON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,469
- **Award type:** 5
- **Project period:** 2018-07-25 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971523

## Citation

> US National Institutes of Health, RePORTER application 9971523, LncRNA H19 in Cholestatic Liver Diseases (5R01DK115377-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971523. Licensed CC0.

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