Investigator: Nisanne Ghonem, University of Rhode Island

Scientific Theme: Molecular Toxicology

Abstract:  Chronic cholestatic liver disease results from an impairment of bile production and causes intracellular retention of bile acids (BAs) and subsequent cytotoxicity. Accumulation of toxic BAs is a significant contributor to disease progression. Cholestasis is characterized by inflammation and the destruction of hepatic bile ducts, for which no curative therapy exists. Complications of unresolved disease include prolonged inflammation, contributing to fibrosis, cirrhosis, and a high risk for malignancies. Very few therapies are FDA-approved for cholestasis, such as ursodeoxycholic acid (UDCA), and some patients only partially respond to it while more advanced cases often do not, and survival for some is not improved. Alternative strategies to reduce BA toxicity and inflammation would serve mechanistic approach to immediately improve patient symptoms while minimize disease progression and significantly delay time to transplantation.

Peroxisome proliferator-activated receptor-alpha (PPARa) is a nuclear hormone receptor highly expressed in the liver where it has a critical role in cholesterol, lipid, and BA homeostasis by regulating transcription of genes responsible for BA synthesis, metabolism, and detoxification. PPARα also inhibits inflammation by blocking NF-κB signaling via up-regulation of inhibitory proteins, IκB. Non-cholestatic volunteers showed that fenofibrate (FF), a PPARa agonist, improves serum BA composition, rendering bile less toxic. We hypothesize that fenofibrate activates PPARα to promote BA detoxification and reduce hepatic inflammation by up-regulating IκB to inhibit NF-κB-mediated transactivation of inflammatory cytokines.

Specific aim 1 will characterize the effects of FF on BA regulation and glucuronidation. An LC-MS/MS assay will be developed to measure serum concentrations of free and conjugated primary and secondary BA and their glucuronide metabolites from cholestatic patients pre- and post-FF therapy.

Specific aim 2 will examine the inhibitory role of FF against NF-κB-mediated inflammation. Serum pro-inflammatory cytokine (TNFα, IL- 1β, and IL-8) concentrations will be measured from cholestatic patients pre- and post-FF therapy by ELISA. Additional in vitro studies will be performed to examine the regulatory pathways of PPARα in mediating the anti-inflammatory effects. This research will significantly impact the field of liver health by providing immediate symptom relief and improving survival for patients with cholestatic liver injury. Also, this research will support further investigation of nuclear receptors as therapeutic targets for other liver diseases characterized by BA toxicity and inflammation, i.e. nonalcoholic fatty liver disease or non-alcoholic steatohepatitis.

Human Health Relevance:  Cholestatic liver disease results from a disruption in bile production and causes toxic levels of bile acids (BAs) in liver and the blood as well as inflammation. The only treatment available is liver transplantation. This project will test a PPARa targeted therapy to reduce BA toxicity and inflammation, in effort to reduce liver disease and cholestatic liver injury. Collectively, this work makes significant contributions to the field of liver medicine and potentially offers patients a new therapy for cholestasis.