Dr. Kari Nejak-Bowen, Associate Professor of Pathology and director of the PLRC Enrichment Program along with Dr. Paul Monga, Chair of Experimental Pathology and Director of the PLRC, were awarded a multiple PI grant from the NIH-NIDDK on their project investigating “The role and regulation of beta-catenin in cholestatic liver disease.”


Chronic cholestasis results from bile secretory defects or impairment of bile flow, and there are few effective medical therapies available. During the past funding period, we have made significant progress in determining the multifactorial role of the Wnt/b-catenin pathway in cholestatic liver disease (CLD). We show b-catenin inhibition decreases bile acid (BA) synthesis, limiting CLD and fibrosis after bile duct ligation. However, inhibition of b-catenin in the Mdr2 knockout (KO) mice, a model mimicking Primary Sclerosing Cholangitis (PSC), aggravated rather than alleviated injury. In fact, Mdr2-b-catenin-KO (DKO1) mice more closely resembled PSC cases than Mdr2 KO, suggesting this might be a clinically relevant model to study biology and therapeutics for PSC. b-catenin is also a critical component of adherens junctions (AJs), where its loss is compensated by spontaneous increase in g-catenin. We show that deletion of both b- & g-catenin from hepatocytes (HCs) & cholangiocytes (CCs) in DKO2 mice resulted in CLD, failure to thrive, increased BA, fibrosis, and mortality, and resembled progressive familial intrahepatic cholestasis (PFIC), a pediatric CLD. Although DKO1 and DKO2 had a disparate underlying basis, they share phenotypic commonalities including loss of hepatocyte differentiation & acquisition of mesenchymal characteristics; loss of cell polarity; and pertubations in cell-cell junctions. Intriguingly, none of these events have been studied in great depth in CLD and cholangiopathies, making our study innovative and significant. Based on these findings, we hypothesize that our DKO models represent a subset of PSC and PFIC cases which will be validated by transcriptomic analyses. Regardless of the disease subtype, these mice serve as powerful pre-clinical models for in-depth mechanistic studies of processes such as cell maturation/differentiation, cell polarity and/or cell-cell junctions, that are less well investigated and understood in disease pathogenesis. We further posit that modulating the determinants of key processes such as TGFb signaling & b-catenin in both HCs & CCs, will not only provide novel insights into the role of b-catenin in cell polarity and cholangiocyte biology, but might also have major therapeutic implications in the general context of cholangiopathies. We are proposing 3 independent yet cohesive aims to test our hypothesis. In Aim 1, we will validate the relevance of the DKO1 and DKO2 models to human CLD subclasses. In Aim2, we will investigate the role of TGFb in progressive CLD models associated with b-catenin loss, since both our preclinical models are characterized by increased TGFb signaling and ensuing loss of cell polarity with enhanced expression of epithelial-to-mesenchymal transition (EMT) markers. In aim 3, we will determine the role of CC b-catenin in Mdr2 KO mice by its deletion from this cell type. We will also study the impact of dual deletion of b-g-catenin in CC. Thus our proposed studies will comprehensively address the 3 poorly understood processes of epithelial to mesenchymal reprogramming,  loss of cell polarity, and perturbations in cell-cell junctions, in the pathogenesis of CLD.