Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease of unknown etiology characterized by progressive inflammation and fibrosis of the intrahepatic and extrahepatic biliary ducts. Currently, there are no effective medical therapies available, and liver transplantation remains the only life-extending treatment option for patients with end-stage PSC. Despite extensive research, the pathogenetic mechanisms of PSC are still incompletely understood. One mechanism that is highly relevant is the accumulation of toxic bile acids (BA) in the liver. We have recently demonstrated that liver-specific -catenin knockout mice (Alb-cre -catenin KO; KO1) exhibit a dramatic decrease in liver injury, fibrosis, and atypical ductular proliferation (ADP) in two models of cholestasis (bil duct ligation (BDL) and 0.1% 3,5- diethoxycarbonyl-1,4-dihydro-collidine (DDC) diet). Furthermore, we observed decreased total hepatic BA in KO1 after BDL, concomitant with enhanced farnesoid X receptor (FXR) activation. This led to the discovery of a novel role for -catenin in regulating BA synthesis and transport through association with FXR in the nucleus. Furthermore, inhibition of -catenin activates a pool of FXR that is normally unresponsive to BA stimulation. Thus, the overarching hypothesis of the proposal is that suppressing -catenin during cholestasis may alleviate injury and progression of the disease through inhibition of BA biosynthesis by physically inhibiting FXR activation. Further, strategies that suppress -catenin could potentially be used in conjunction with current therapeutics that utilize FXR agonists in order to enhance the effectiveness of treatment.
In aim 1, we will investigate the impact of reduced BA toxicity through -catenin knockdown on murine cholestatic liver injury. We hypothesize that reduction of toxic BA through -catenin inhibition would delay the onset or alleviate the severity of disease in obstructive, chemical, and genetic models of cholestasis.
In aim 2 we will characterize the role and regulation of FXR/-catenin association in cholestasis. This will be accomplished by first verifying FXR activation as the protective mechanism after BDL through use of FXR--catenin double KO mice, and then analyzing the dynamics of FXR/-catenin association and activity during cholestasis. We will also determine the contribution of upstream Wnt signaling to FXR/-catenin association both in vivo and in vitro.
In aim 3, we will determine the therapeutic and prognostic relevance of FXR/ -catenin association. First, we will directly compare the exogenous inhibition of -catenin in conjunction with an FXR agonist to the use of agonist alone in alleviating cholestatic injury. Finally, we will correlate -catenin localization as a surrogate for FXR activity with hepatic function in PSC patient biopsies post-transplant. Thus, the proposed studies in the grant will further our understanding of the role of -catenin in cholestatic diseases such as PSC and the expected outcomes may have significant prognostic and therapeutic implications.

Public Health Relevance

The research proposal focuses on the feasibility of inhibiting -catenin in cholestatic liver diseases such as primary sclerosing cholangitis (PSC) as well as understanding the mechanisms that regulate the improvement in phenotype and amelioration of injury in models of PSC where -catenin is inhibited or absent. The correlation between -catenin activation/localization and hepatic functions in PSC patients will also be addressed.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Burgess-Beusse, Bonnie L
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University of Pittsburgh
Schools of Medicine
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Thompson, Michael D; Moghe, Akshata; Cornuet, Pamela et al. (2018) ?-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. Hepatology 67:955-971
Nejak-Bowen, Kari; Moghe, Akshata; Cornuet, Pamela et al. (2017) Role and Regulation of p65/?-Catenin Association During Liver Injury and Regeneration: A ""Complex"" Relationship. Gene Expr 17:219-235
Okabe, Hirohisa; Yang, Jing; Sylakowski, Kyle et al. (2016) Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 64:1652-1666