Pictured left to right: K. Nejak-Bowen, J. Locker, X. Ma, P. Monga
Saggi, H., Maitra, D., Jiang, A., Zhang, R., Wang, P., Cornuet, P., Singh, S., Locker, J., Ma, X., Dailey, H., Abrams, M., Omary, M.B., Monga, S.P., Nejak-Bowen, K., Loss of hepatocyte β-Catenin protects mice from experimental porphyria-associated liver injury, Journal of Hepatology (2018), doi: https://doi.org/10.1016/j.jhep.2018.09.023
ABSTRACT:
Background & Aims
Porphyrias occur from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet, which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/β-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury.
Methods
β-catenin knockout (KO) mice, Wnt co-receptor KO mice, and littermate controls were fed DDC diet for 2 weeks. β-catenin was exogenously inhibited in hepatocytes by administering β-catenin DsiRNA conjugated to a lipid nanoparticle (LNP) to mice after DDC diet, and weekly afterwards for 4 weeks. In all experiments, serum and liver were collected; liver was analyzed by histology, Western blotting, and real-time PCR. Porphyrin was measured by fluorescence, quantification of polarized light images, and liquid chromatography mass spectrometry.
Results
DDC-fed mice lacking β-catenin or Wnt signaling had decreased liver injury compared to controls. Exogenous β-catenin suppression by DsiRNA during DDC feeding also showed less injury as compared to control LNP. Control livers contained extensive porphyrin deposits which were largely absent in mice lacking β-catenin signaling. Notably, we identified a network of key heme biosynthesis enzymes that are suppressed in the absence of β-catenin, preventing accumulation of toxic protoporphyrins. Additionally, mice lacking β-catenin exhibited fewer protein aggregates, improved proteasomal activity, and lesser induction of autophagy, all contributing to protection from injury.
Conclusions
β-catenin inhibition, through its pleiotropic effects on metabolism, cell stress, and autophagy, represents a novel therapeutic approach for porphyria patients.
Lay Summary
Porphyrias are disorders resulting from abnormalities in the steps that lead to heme production, which cause buildup of toxic by-products called porphyrins. Liver is commonly either a source or a target of excess porphyrins, and complications can range from minor abnormalities to liver failure. In this report, we inhibited Wnt/β-catenin signaling in an experimental model of porphyria, which resulted in decreased liver injury. Targeting β-catenin affected multiple components of the heme biosynthesis pathway, thus preventing buildup of porphyrin intermediates. Our study suggests that drugs inhibiting β-catenin activity could reduce the amount of porphyrin accumulation and help alleviate symptoms in patients with porphyria.
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