A team of researchers has discovered a molecular missing link that helps explain why fasting brings on acute attacks of the genetic disease hepatic porphyria, according to a new report in the 26 August issue of the journal Cell. The finding could help improve treatments for those suffering from the disease, which may have been the culprit behind the "madness" of King George III of England.
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.
"Unfortunately, because of the therapeutic high carbohydrate intake, patients with hepatic porphyrias are prone to weight gain. Losing excess weight is very difficult for some of these patients because of fasting-induced acute attacks. Hopefully, our findings described here might lead to the development of more specific treatments for these patients," Spiegelman and colleagues say.
However, since fasting boosts PGC-1a levels, "it is also important that patients not fast or strongly diet," Spiegelman adds.
The researchers tested the link between PGC-1a and ALAS-1 in mice engineered to lack PGC-1a in the liver. In these mice, ALAS-1 levels did not rise as dramatically as in normal mice after fasting or after chemical treatment that mimicked some of the enzyme defects in genetic porphyria.
Although drugs like alcohol and barbiturates can also provoke an acute porphyria attack, PGC-1a is not involved in attacks brought on by barbiturates, Spiegelman and colleagues found after examining the effects of phenobarbital in both normal mice and mice without PGC-1a in their livers.
Acute porphyria attacks can include severe abdominal pain, skin sensitivity to sunlight, and psychiatric disorders like hysteria, which may have been the source of King George III's well-known insanity, according to some historians.
The other members of the Spiegelman research team include Christoph Handschin, Jiandie Lin, James Rhee, Sherry Chin, Pei-Hsuan Wu, and Anne-Kathrin Peyer and Urs Meyer of the University of Basel in Basel, Switzerland. The study was supported by the National Institutes of Health and the Swiss National Science Foundation.
Handschin et al.: "Nutritional Regulation of Hepatic Heme Biosynthesis and Porphyria through PGC-1a" Publishing in Cell, Vol. 122, pages 505-515, August 26, 2005, DOI 10.1016/j.cell.2005.06.040. www.cell.com