Harvinder Saggi, An Jiang, Satdarshan Pal Singh Monga, Kari Nejak-Bowen Department of Pathology, University of Pittsburgh School of Medicine, PIttsburgh, PA 15261

Intermittent cholestasis can be induced in mice by administration of a diet containing the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC causes accumulation of porphyrin intermediates that results in biliary injury. We have previously shown that mice lacking b-catenin in liver have lesser ductular proliferation than wild-type (WT) mice when fed DDC diet for 4 weeks. To determine if this was due to lesser injury, we analyzed WT and beta-catenin knockout (KO) mice after 2 weeks of DDC. We found that KO mice had less liver injury compared to WT, as well as lower liver weight to body weight ratios and lesser fibrosis. To strengthen these observations, we exogenously inhibited beta-catenin in hepatocytes by administering either beta-catenin shRNA conjugated to a lipid nanoparticle (LNP) or control LNP to mice weekly after DDC. After 4 weeks, mice treated with beta-catenin LNP phenocopied many aspects of KO mice treated for 2 weeks. Intriguingly, mice fed DDC and treated with beta-catenin LNP also had significantly smaller, lighter-colored livers than DDC alone. Upon histological examination, the control mice contained brown deposits characteristic of porphyrin accumulation, which were largely absent in beta-catenin LNP-treated mice. To determine the mechanism of decreased porphyrin, we examined expression of heme biosynthesis enzymes. We found a decrease in two enzymes that catalyze the earliest steps in the pathway in mice treated with DDC + beta-catenin LNP compared to DDC alone. On the other hand, expression of Cyp3a1, which metabolizes DDC and has been shown to correlate with decreased injury, is increased after beta-catenin inhibition. Thus, we have identified a protective effect of inhibiting beta-catenin in a model of cholestasis and porphyria, which is due to a decrease in components of the heme biosynthesis pathway resulting in decreased accumulation of intermediate protoporphyrins, and may represent a potential new treatment for intermittent porphyria in patients.

Additional Abstract Information

Presenter: Harvinder Saggi

Institution: University of Pittsburgh

Type: Poster

Subject: Biology

Status: Approved

Time and Location

Session: Poster 9
Date/Time: Fri 4:00pm-5:00pm
Location: Wellness Center - Tripod 46 Side C