Porphyria disease is caused by defects in the enzyme pathway that produces heme, a critical iron compound found throughout the body, most notably in red blood cells. The defects lead to the overproduction and toxic accumulation of the intermediate molecules that eventually become heme. Researchers and physicians have long known that fasting can cause acute attacks of the disease, and that the attacks can be relieved with glucose or other high-carbohydrate treatments, but the exact link between fasting and the attacks has been mysterious until now.
In the Cell study, Bruce Spiegelman of the Dana-Farber Cancer Institute and Harvard Medical School and colleagues show that fasting increases levels of a metabolic protein called PGC-1a. The "starvation" signal that fasting sends throughout the body prompts PGC-1a to jump-start the process of creating glucose from scratch in the liver. However, PGC-1a also regulates the activity of an enzyme called ALAS-1, the first key enzyme in the heme production pathway.
The higher levels of PGC-1a produce higher levels of ALAS-1, leading to a toxic buildup of precursor heme molecules, Spiegelman and colleagues found.
The finding explains why glucose infusions are helpful in treating acute attacks since the glucose boost can shut off the starvation signal and return PGC-1a levels back to normal.
However, the discovery could pave the way for new porphyria therapies that focus on PGC-1a itself rather that relying on high-carbohydrate treatments, the researchers suggest.