# The role of lymphatics in cholestatic liver disease

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $692,243

## Abstract

SUMMARY
 Cholestatic liver diseases such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis
(PBC) are autoimmune liver diseases with limited treatment options. Lymphatic vessels, located in the vicinity
of bile ducts, help to reduce inflammation by removing cellular waste materials and inflammatory immune cells
from the liver. Further, lymphatic endothelial cells (ECs) likely have contact with bile acids, as bile acids and
bilirubin have been observed in lymph of animals with cholestasis. The role of the hepatic lymphatic system in
cholestatic liver disease is largely unknown, and so are the effects of bile acids on lymphatic EC functions.
The goal of this proposed study is to explore the potential of increasing lymphatic vessels as a therapeutic
option for cholestatic liver diseases and understand this healing process with a focus on the microenvironment
and the molecular mechanisms underlying lymphangiogenesis (formation of new lymphatic vessels).
 Our preliminary studies showed that lymphatic vessel numbers were significantly increased in mouse
models of cholestatic liver disease. We have also found that promoting lymphangiogenesis through
overexpression of vascular endothelial growth factor C (VEGF-C), the most potent lymphangiogenic factor, can
significantly decrease liver fibrosis and injury in mice with cholestasis, suggesting a beneficial role of lymphatic
vessel formation in cholestatic livers. Further, we have determined that liver lymphatic ECs express bile acid
receptors, such as Takeda G protein-coupled receptor 5 (TGR5), and significantly proliferate in response to
bile acids such as taurolithocholic acid (TLCA) and taurodeoxycholic acid (TDCA), known to have a strong
affinity to TGR5. These observations have led us to hypothesize that hepatic lymphatic vessels may exert a
beneficial effect on cholestatic liver injury and that certain hydrophobic bile acids may be novel pro-
lymphangiogenic factors. To test these hypotheses, we propose three Aims: 1) determine the role of the
hepatic lymphatic system in cholestatic liver disease, 2) determine the mechanism of bile acid-driven hepatic
lymphangiogenesis, and 3) determine the spatial and temporal regulation of lymphatic vessels and their impact
on the progression of cholestatic liver disease.
 The proposed study will determine whether hepatic lymphatic vessels work to ameliorate cholestatic
liver disease and whether boosting lymphangiogenesis and lymphatic drainage could be a new therapeutic
option for this disease.

## Key facts

- **NIH application ID:** 10997767
- **Project number:** 1R01DK138584-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YASUKO IWAKIRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $692,243
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997767

## Citation

> US National Institutes of Health, RePORTER application 10997767, The role of lymphatics in cholestatic liver disease (1R01DK138584-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997767. Licensed CC0.

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