Suppressing Liver Signaling Pathway May Help to Treat Porphyria

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Suppressing Wnt/beta-catenin — a signaling pathway that plays a key role in liver health — significantly reduced liver damage and the porphyrin deposits whose accumulation cause porphyria in a mouse model of the disease, a study shows.

Notably, these beneficial effects were associated with lower levels of enzymes involved in the production of porphyrins and with greater autophagy, a form of cellular recycling, including of toxic deposits, needed to maintain healthy processes.

These findings call for further evaluation of Wnt/beta-catenin suppression as a potential therapy for porphyria.

Results of the study “Beta-catenin inhibition as a novel therapeutic strategy for porphyria” were presented by Anu Balogun, a PhD candidate in Kari Nejak-Bowen’s lab at the University of Pittsburgh School of Medicine (UPSM), at the 2022 Experimental Biology meeting, held in Philadelphia April 2–5.  Nejak-Bowen, PhD, is an associate professor of pathology at UPSM.

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Porphyrins are molecules that go through several chemical changes to produce heme, a component of several proteins, such as hemoglobin, that is required for blood oxygen transport in the body.

Porphyria comprises a group of disorders caused by the toxic buildup of porphyrins and their precursors in several tissues and organs, such as the liver, kidneys, and skin, due to defects in any of the enzymes involved in the heme production pathway.

This toxic accumulation of heme precursors “can cause cellular abnormalities such as oxidative stress, mitochondrial dysfunction, protein aggregation and inhibition of crucial functions such as autophagy,” the researchers wrote.

Oxidative stress if a type of cellular damage resulting from an imbalance between the production of potentially harmful oxidant molecules and cells’ ability to clear them with antioxidants. Mitochondria, the cells’ powerhouses, are the compartments where heme production partly takes place inside cells, and autophagy is a pathway by which cells break down unwanted proteins and other cellular components.

Since the liver is both a source and a sink for porphyrins, Balogun and lab colleagues evaluated whether the Wnt/beta-catenin pathway, which plays a key role in liver health and disease, could also regulate heme production in the liver.

Activation of Wnt cell surface receptors cause a cascade of events that leads to the release of the beta-catenin protein from a suppressed state, allowing it to activate target genes. As such, beta-catenin suppression is commonly used to block Wnt activation effects.

Researchers analyzed the effects of treating a mouse model of liver porphyria with fatty, tiny particles filled with RNA molecules designed to specifically suppress beta-catenin production.

These mice develop liver porphyria-like symptoms after being fed with a diet containing 3,5-Diethoxycarbonyl-1,4-Dihydrocollindine (DDC), an additive whose metabolism leads to the suppression of the terminal enzyme in the heme production pathway.

Results showed that beta-catenin suppression significantly reduced liver injury and the number of porphyrin deposits in the animals, suggesting that this approach provides protection from DDC-induced injury by lowering porphyrin accumulation in the liver.

This drop in porphyrin deposits was associated with significantly reduced levels of ALA-S and ALA-D, the enzymes involved in the first and second steps of heme production, respectively, and resulting in the production of porphyrins.

Further analysis showed that the gene providing instructions to produce ALA-D contained a region where a component of the Wnt/beta-catenin pathway binds to and regulates its activity. This implicated ALA-D as a direct Wnt/beta-catenin target.

These findings highlighted “a novel role of the Wnt/beta-catenin pathway in regulating heme biosynthesis by inhibiting early steps in heme biosynthesis pathway and reducing toxic porphyrin accumulation,” the researchers wrote.

In addition, beta-catenin-deficient mice showed increased autophagy, which likely contributes to the approach’s protective effects by helping cells clear accumulated porphyrins.

“These observations collectively offer a novel opportunity to remedy porphyria by targeting the Wnt/beta-catenin signaling pathway,” with several Wnt pathway suppressors already being tested on other diseases in clinical trials, the team wrote.

The team now plans to conduct additional studies to further validate ALA-D as the mechanistic target of beta-catenin in the heme production pathway and better understand the link between Wnt/beta-catenin pathway and autophagy in porphyria.