Highlights
- •Porphyrias are caused by defects in heme biosynthesis, which can lead to cholestasis, inflammation, and fibrosis.
- •The Wnt/β-catenin pathway plays a role in pathological processes in the liver, including cholestasis and biliary injury.
- •Inhibiting β-catenin in a mouse model of porphyria resulted in decreased liver injury.
- •Several key heme biosynthesis enzymes were downregulated in livers lacking β-catenin signaling.
- •Mice lacking β-catenin had fewer protein aggregates, resulting in improved proteasomal activity and less autophagy.
Background & Aims
Porphyrias result from anomalies of heme biosynthetic enzymes and can lead to cirrhosis
and hepatocellular cancer. In mice, these diseases can be modeled by administration
of a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), 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 (Ctnnb1) knockout (KO) mice, Wnt co-receptor KO mice, and littermate controls were fed a
DDC diet for 2 weeks. β-Catenin was exogenously inhibited in hepatocytes by administering
β-catenin dicer-substrate RNA (DsiRNA), conjugated to a lipid nanoparticle, to mice
after DDC diet and then weekly for 4 weeks. In all experiments, serum and livers were
collected; livers were 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 mice that underwent β-catenin suppression by DsiRNA during
DDC feeding also showed less injury compared to control mice receiving lipid nanoparticles.
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 reduced 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 patients with porphyria.
Lay summary
Porphyrias are disorders resulting from abnormalities in the steps that lead to heme
production, which cause build-up 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 build-up 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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: October 01, 2018
Accepted:
September 18,
2018
Received in revised form:
August 30,
2018
Received:
April 9,
2018
Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
