The role of lymphatics in cholestatic liver disease

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.