UPMC Children’s GI Researchers Contribute to Important New Study Uncovering Novel Insights into the Mechanisms of Action of 24-norUrsodeoxycholic Acid as a Therapeutic Option for Cholestatic Liver Disease

Cholestatic liver diseases are the most common form of liver disease observed in pediatric patients.

Bile acids manufactured in the liver are essential for the digestion and absorption of lipids, and the proper flow or transport of bile from the liver to the digestive tract is crucial for both absorption of nutrition in the gut and maintaining the health of the liver. Disruptions in flow due to blockages or other factors lead to cholestasis, which creates havoc with nutritional health and poses serious long-term consequences for the liver, including chronic liver disease and liver failure.

One of the essential bile acids that contribute to normal bile production and transport is ursodeoxycholic acid (UDCA), which is manufactured in minimal quantities by the liver.

A synthetic form of this bile acid, acid, 24-norUrsodeoxycholic acid (norUDCA), has been created and was found to have significant positive effects on promoting bile transport, reducing inflammation, and mitigating cholestasis in preliminary trials.

The mechanism underlying these positive effects on the liver has previously been unknown. That is until now with the publication of a new paper in JCI Insight by a multicenter research team that includes UPMC Children’s Hospital of Pittsburgh Division of Gastroenterology, Hepatology and Nutrition researchers from the Feranchak Laboratory. Division chief Andrew Feranchak, MD, and Qin Li, PhD, contributed to the study.

Dr. Feranchak's lab studies the mechanisms of hepatobiliary transport in an effort to identify new treatments for cholestatic liver disease. His team joined the research project because of their expertise and prior first identification of an important chloride ion channel at work in the biliary duct epithelium called TMEM 16A.

Study Overview and Clinical Implications

This new study delved into the properties and actions of norUDCA. The study aimed to understand the molecular mechanisms behind the bile acid's impact on bile flow.  The results revealed that norUDCA does not require the involvement of some major bile acid carriers to stimulate secretion and increase bile flow.

The research team examined how norUDCA interacts with specific proteins involved in bile acid transportation. The study found that norUDCA activates TMEM16A in cells lining the bile ducts. Activation of TMEM16A increases secretion leading to an enhanced bile flow.

Interestingly, the study demonstrated that norUDCA activates TMEM16A directly and does not require the activity of other major bile acid transporters. This means that norUDCA can directly increase bile flow and secretion without relying on these other transporters.

These findings support further investigation and translation of the therapeutic potential of norUDCA in cholestatic liver disease. This research could ultimately lead to the development of novel treatment strategies for children and adults suffering from cholestatic liver diseases.

Read the full text of the study using the link below.

Reference

Truong JK, Li J, Li Q, Pachura K, Rao A, Gumber S, Fuchs CD, Feranchak AP, Karpen SJ, Trauner M, Dawson PA. Active Enterohepatic Cycling Is not Required for the Choleretic Actions of 24-norUrsodeoxycholic Acid in Mice. JCI Insight. 2023; 8(6): e149360.