Mouse study: Genes, diet may shape risk for common porphyria
Some mice, not others, develop PCT after exposure to environmental triggers
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A study in mice suggests that genetic makeup and diet may influence a person’s susceptibility to developing sporadic porphyria cutanea tarda (PCT), the most common form of porphyria, after exposure to environmental triggers.
When researchers exposed mice to excess iron, a known trigger of PCT, only some developed the disease, depending on their genetic makeup. The vulnerable mice showed changes in levels of several genes that help liver cells maintain a healthy internal chemical balance. These changes may make early building blocks of heme — a molecule the body needs to carry oxygen in the blood, but whose production is disrupted in PCT — more likely to undergo harmful chemical changes. In PCT, these altered molecules can build up in the liver and contribute to disease symptoms. A similar effect was observed in mice fed a high-protein, high-fat diet.
The findings “illustrate the interaction” of multiple genes, environmental factors, and diet in mice models of sporadic PCT, the researchers wrote.
The study, “Genetic traits and diet triggering the iron-induced hepatic model of the idiopathic disorder sporadic porphyria cutanea tarda,” was published in the journal Free Radical Biology and Medicine.
PCT is caused by disruptions in heme production. In familial, or inherited, forms, these originate from mutations in the UROD gene, which provides instructions for making an enzyme needed to produce heme. When this enzyme doesn’t function properly, heme-building molecules called porphyrins accumulate, mainly in the liver and skin, leading to liver damage and skin-related porphyria symptoms.
Why are some more vulnerable than others?
Unlike inherited forms, sporadic PCT usually develops after exposure to external risk factors such as alcohol use, estrogen-containing medications, and hepatitis C infection. It is also strongly linked to iron overload — a condition in which too much iron builds up in the body, especially in the liver, where it can cause damage.
However, not everyone exposed to these triggers develops the disease. Why some people are more vulnerable than others remains unclear, the researchers said.
Previous studies have shown that in certain genetically susceptible mice, iron alone can trigger a liver disorder called uroporphyria, which closely resembles sporadic PCT.
The researchers sought to determine whether susceptibility to iron-induced PCT-like disease in mice is driven by a single gene or by multiple genes acting in combination.
The team used mouse strains already known to respond differently to iron. Some develop uroporphyria after iron treatment, while others remain resistant. The team then bred a sensitive strain with a resistant one to produce offspring with a mix of genes from both parents.
When these offspring were given excess iron, along with a compound that speeds up uroporphyria development, their responses varied widely. Some developed high levels of uroporphyrins in the liver, a sign of uroporphyria, while others showed little or no disease.
Using genetic mapping, a method that links physical traits to specific DNA regions, the researchers identified three main regions of the mice’s genome associated with disease risk. These regions — on chromosomes 1, 11, and 17 — appeared to harbor multiple genetic differences that, together, influenced how strongly the mice developed uroporphyria.
When the team examined gene activity in the liver, they identified several genes whose activity differed between mice with severe disease and those that remained resistant.
Within the three genetic risk regions, the largest changes were observed in genes involved in regulating the cell’s internal chemical environment and in managing iron metabolism.
Within the chromosome 1 region, one gene in particular, Glul, stood out. This gene provides instructions for making an enzyme that helps liver cells maintain a healthy chemical balance. In the study, Glul was consistently less active in mice that developed uroporphyria.
Reduced Glul activity may disturb the cell’s normal chemical balance, promoting a more oxidizing environment. Such conditions make it easier for sensitive molecules like uroporphyrinogen — a precursor in heme production — to react with oxygen and build up as harmful porphyrins.
In contrast, genes directly involved in making heme, including UROD, did not show major differences.
Richer diet linked to increased gene activity
Finally, the team found that diet strongly affected disease development. Mice fed the richer laboratory diet developed clear uroporphyria after iron treatment, while those on the leaner diet showed little to no disease, even though both groups had similar levels of iron in their livers.
The richer diet contained more fats, proteins, vitamins, and certain minerals, and provided more usable energy. This diet was linked to higher activity of Alas1, a gene that controls the first step in heme production. Increased Alas1 activity may push more precursors through the heme-making pathway, raising the chance that these molecules build up when later steps do not work efficiently.
The richer diet was also associated with reduced Glul activity, suggesting a liver environment that promotes uroporphyrinogen oxidation and favors porphyrin accumulation.
“This study demonstrates the complexity of gene/environment/diet effects of the mouse models of sPCT and illustrates the importance of understanding such interactions for toxic and idiopathic human disorders,” the researchers wrote.
