PGC-1 mediates effects of nutrition on blood disease porphyria
Dana-Farber Cancer Institute researchers say they have uncovered a molecular explanation for the episodic attacks of irrational and demented behavior in porphyria, the disease believed to have afflicted "Mad" King George III, the British ruler blamed for the loss of the American colonies in the Revolutionary War.
The mental and physical symptoms of porphyria, a rare genetic blood disease which a number of modern researchers believe plagued King George intermittently throughout his tumultuous reign, can be brought on by fasting and exposure to certain drugs, and is successfully treated by feedings of sugar and high-carbohydrate food. A biological explanation for these nutritional effects has been lacking.
The Dana-Farber scientists say in a report featured on the cover of the August 26 issue of Cell that the nutritional component of porphyria involves a key master metabolic molecule, PGC-1 alpha, in cells of the liver. The gene that makes PGC-1 alpha was isolated in 1998 in the laboratory of Bruce Spiegelman, PhD, who is senior author of the new report. Postdoctoral fellow Christopher Handschin, PhD, is lead author.
"We've explained how porphyria symptoms can occur in episodic attacks triggered by fasting, and why they can be treated by feeding carbohydrates and glucose," says Spiegelman.
King George III suffered from five prolonged, severe episodes of madness during his rule from 1760 to 1820, a period in which he both expanded the British Empire and so stubbornly refused to negotiate with the rebellious American Colonists that they felt only a revolution against England could resolve their grievances. The symptoms recorded at the time sound to modern diagnosticians as typical of porphyria, though the King's attacks were unusual in their severity and that they didn't appear until he was 50.
Several types of porphyria exist, all of them stemming from inherited mutations that disrupt the body's manufacture of heme. A reddish pigment that contains iron, heme is a building block of the oxygen-carrying hemoglobin in red blood cells. The complex synthesis requires eight different enzymes, and when any of them is deficient because of a mutation, the process is blocked. The resulting back up of "precursor" substances is toxic, and can cause a range of symptoms, including dark colored urine, abdominal pain, nausea, vomiting, constipation, weakness in the limbs, and psychiatric symptoms such as confusion, fits and hallucinations.
Earlier this year, the British journal Lancet published a report saying that a test of strands of George III's hair contained arsenic, which can provoke porphyria attacks. The authors of that report suggested that, ironically, he may have been exposed to arsenic contamination of a substance his doctors gave him as treatment.
PGC-1 alpha is a "transcriptional coactivator" that acts as an on-off switch for a number of genes involved in manufacture of glucose in the liver and in the "heating system" of brown fat cells that help prevent damage from cold in certain animals.
With their intimate knowledge of PGC-1 alpha and its varied roles in energy metabolism, the Dana-Farber researchers wondered if it might be involved in porphyria, since PGC-1 alpha is a regulator of heme manufacture in the liver. One of its actions is controlling the activity of the ALAS-1 gene that makes a protein that's crucial to the normal manufacture of heme. A defect in this genetic signaling pathway could cause ALAS-1 to accumulate in high levels, leading to the symptoms of porphyria attacks.
"We found that PGC-1 alpha is an important factor controlling the expression of ALAS-1 in the fasted and fed liver," the authors write. "Moreover, we showed that hepatic [in the liver] PCG-1 alpha is a major determinant of the severity of acute porphyric attacks in mouse models of chemical porphyria."
Through a series of experiments with normal mice and those engineered to lack the PGC-1 alpha gene, the researchers said they have provided "a clear-cut mechanism" linking fasting to an increase in PGC-1 alpha, and, in turn, overactivity of the ALAS-1 gene. The therapeutic effect of glucose and high-carbohydrate diets on porphyria, they add, occurs because glucose causes the pancreas to make more insulin, which results in suppression of the PGC-1 alpha gene.
The findings suggest that patients with porphyria should avoid any drugs or foods that turn on PGC-1 alpha activity in the liver, the researchers say. There could be implications for treatment as well: high-carbohydrate diets aren't a satisfactory therapy for affected patients as it make them gain, and fasting in order to lose the weight risks provoking attacks. Hopefully, the researchers say, it might be possible to develop more specific treatments now that the mechanism underlying the symptoms of porphyria is better understood.
Source : Dana-Farber Cancer Institute